7-benzyl-4-(methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-A]pyrido[3,4-E]pyrimidin-5 (1H)-one, salts thereof and methods of using the same in combination therapy

ABSTRACT

This disclosure relates, at least in part, to a method of treatment. In one embodiment, the method of treatment comprises administering to a subject in need of such treatment a first therapeutic agent including compound (1): 
                         
or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent, wherein the first therapeutic agent and the second therapeutic agent are administered either simultaneously or sequentially.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/100,045, filed Aug. 9, 2018, which is continuation of U.S. patentapplication Ser. No. 15/626,518, filed Jun. 19, 2017, now U.S. Pat. No.10,045,992, which is a continuation of U.S. patent application Ser. No.15/036,210, filed May 12, 2016, now U.S. Pat. No. 9,688,679, which is aNational Phase Application of PCT International Application No.PCT/US2014/055373, filed Sep. 12, 2014, which is a continuation-in-partof U.S. patent application Ser. No. 14/341,392, filed Jul. 25, 2014, nowU.S. Pat. No. 9,376,437, and International Patent Application No.PCT/US2014/048241, filed Jul. 25, 2014, each of which is acontinuation-in-part of U.S. patent application Ser. No. 14/208,657,filed Mar. 13, 2014, now U.S. Pat. No. 9,265,765, which in turn claimsthe benefit of U.S. Provisional Patent Application No. 61/779,828, filedMar. 13, 2013, and U.S. Provisional Patent Application No. 61/904,718,filed Nov. 15, 2013, all of which are incorporated herein by referencein their entireties.

BACKGROUND OF THE INVENTION

TNF-related apoptosis-inducing ligand (TRAIL; Apo2L) is an endogenousprotein that selectively induces apoptosis in cancer cells. TRAIL is apowerful inducer of apoptosis in a wide range of human cancer cell linesvia pro-apoptotic death receptor 4 (DR4; TRAIL-R1) and death receptor 5(DR5; TRAIL-R2) at the cell surface through engagement of the extrinsicor intrinsic apoptotic pathways. TRAIL plays a direct role in tumorsuppression during immune surveillance but this anti-tumor mechanism islost during the disease progression. The ability of TRAIL to initiateapoptosis selectively in cancer cells has led to ongoing clinical trialswith administration of recombinant TRAIL and the longer-livedTRAIL-agonist antibodies targeting either of its two pro-apoptotic deathreceptors.

Despite its potency, recombinant TRAIL has efficacy-limiting propertiessuch as short serum half-life, stability, cost, and delivery. Deliveryof recombinant TRAIL or TRAIL-agonist antibodies to the brain is limitedby inability of recombinant TRAIL and TRAIL-agonist antibodies to crossthe blood-brain barrier. Accordingly, there is a continuing need foranti-cancer compositions and methods.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides a pharmaceuticalcomposition, comprising a compound (1):

or a pharmaceutically acceptable salt thereof. In one embodiment, thepharmaceutical composition comprises compound (1) in the form of apharmaceutically acceptable salt thereof. In one embodiment, thepharmaceutical composition comprises compound (1) in the form of apharmaceutically acceptable mono-salt thereof. In one embodiment, thepharmaceutical composition comprises compound (1) in the form of apharmaceutically acceptable di-salt thereof. In one embodiment, thepharmaceutical composition comprises compound (1) in the form of apharmaceutically acceptable salt selected from the group consisting ofhydrochloride, hydrobromide, hydrogensulphate, sulfates, phosphates,fumarates, succinates, oxalates and lactates, bisulfates, hydroxyl,tartrate, nitrate, citrate, bitartrate, carbonate, malate, maleate,fumarate sulfonate, methylsulfonate, formate, acetate, and carboxylate.In one embodiment, the pharmaceutical composition comprises compound (1)in the form of a pharmaceutically acceptable salt selected from thegroup consisting of p-toluene-sulfonate, benzenesulfonate,methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate,glucuronate, ascorbate and maleate. In one embodiment, thepharmaceutical composition comprises compound (1) in the form of apharmaceutically acceptable salt selected from the group consisting ofammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/orwith other counter-ions such as methylamino, dimethylamino, diethylaminoand triethylamino counter-ions. In one embodiment, the pharmaceuticalcomposition comprises compound (1) in the form of a hydrochloridedi-salt or hydrobromide di-salt.

In one embodiment, the pharmaceutical composition of the presentinvention includes a pharmaceutically acceptable carrier.

In some embodiments, a pharmaceutical composition in accordance with thepresent invention includes a second therapeutic agent. In one suchembodiment, the second therapeutic agent is an anti-cancer agent. In oneembodiment, the anti-cancer agent is a mitotic inhibitor. In oneembodiment, the anti-cancer agent is selected from the group consistingof: paclitaxel, docetaxel and a combination thereof. In an alternativeembodiment, the second therapeutic agent is an anti-angiogenic agent. Inone embodiment, the anti-angiogenic agent is bevacizumab. In oneembodiment, the second therapeutic agent is administered as part ofcombination therapy to treat a patient. In one embodiment, details forthe combination therapy is included in the package insert for compound(1).

In some embodiments, the pharmaceutical composition is formulated fororal administration.

In another aspect, the present invention provides a method of treatment.In one embodiment, the method of treatment comprises administering to asubject a pharmaceutical composition, the pharmaceutical compositioncomprising a pharmaceutically effective amount of compound (1):

or a pharmaceutically acceptable salt thereof.

In one embodiment, the method of treatment comprises administering tothe subject a pharmaceutical composition comprising a pharmaceuticallyeffective amount of compound (1) or a pharmaceutically acceptable saltthereof. In one embodiment, the method of treatment comprisesadministering to the subject a pharmaceutical composition comprising apharmaceutically effective amount of compound (1) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

In some embodiments, the method of treatment comprises furthercomprising administering an additional therapeutic agent. In oneembodiment, the additional therapeutic agent includes an anti-canceragent. In one embodiment, the additional anti-cancer agent comprises ananti-mitotic agent. In one embodiment, the additional anti-cancer agentcomprises paclitaxel, docetaxel, bevacizumab or any combinationsthereof.

In one embodiment, the method of treatment further comprises assayingtumor necrosis factor (TNF)-related apoptosis-inducing ligand in asample obtained from the subject undergoing treatment. In oneembodiment, the TNF-related apoptosis-inducing ligand is assayed in ablood sample obtained from the subject.

In one embodiment of the method of treatment in accordance with thepresent invention, the subject undergoing treatment has, or is at riskof having, cancer. In one embodiment, the cancer is selected from thegroup consisting of colon cancer, breast cancer, glioblastomamultiforme, Mantle cell lymphoma, and colorectal cancer.

In one embodiment of the method of treatment in accordance with thepresent invention, the subject is at risk of having cancer. In oneembodiment, the cancer is selected from the group consisting of actinickeratosis, Barrett's esophagus, atrophic gastritis, dyskeratosiscongenital, sideropenic dysphagia, lichen planus, oral submucousfibrosis, solar elastosis, cervical dysplasia, leukoplakia, anderythroplakia.

In one embodiment of the method of treatment in accordance with thepresent invention, the pharmaceutical composition is administered via anoral route of administration. In one embodiment, the pharmaceuticalcomposition is administered via a route of administration selected fromthe group consisting of: rectal, nasal, pulmonary, epidural, ocular,otic, intra-arterial, intracardiac, intracerebroventricular,intradermal, intravenous, intramuscular, intraperitoneal, intraosseous,intrathecal, intravesical, subcutaneous, topical, transdermal,transmucosal, sublingual, buccal, vaginal, and inhalational routes ofadministration.

In one embodiment, the present invention provides a method of treating asubject having, or is at risk of having, brain cancer, the methodcomprising: administering to the subject a pharmaceutical compositioncomprising a pharmaceutically effective amount of compound (1):

or a pharmaceutically acceptable salt thereof. In one embodiment, themethod of treating a subject having, or is at risk of having braincancer, comprises administering to the subject a pharmaceuticalcomposition comprising a pharmaceutically effective amount of compound(1) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

In one embodiment, the present invention provides a method of treatmentcomprising administering to a subject a pharmaceutical composition, thepharmaceutical composition comprising a pharmaceutically effectiveamount of compound (1):

or a pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.

The foregoing summary, as well as the following detailed description ofembodiments of the compositions and methods of treatment, will be betterunderstood when read in conjunction with the appended claims. It shouldbe understood, however, that the invention is not limited to the precisearrangements and instrumentalities described herein.

In another aspect, the present invention provides a method of treatment,which comprises administering to a subject in need of such treatment acombination of a first therapeutic agent including the followingcompound (1) and a second therapeutic agent, the method comprising: (i)administering to the subject the first therapeutic agent includingcompound (1):

or a pharmaceutically acceptable salt thereof; (ii) waiting until apredetermined waiting time has elapsed after the time of administrationof the first therapeutic agent to the subject; and (iii) administeringthe second therapeutic agent to the subject, wherein the predeterminedwaiting time is chosen so as to obtain a delayed therapeutic effect ofthe first therapeutic agent without an increased risk or with a reducedrisk of possible combined toxic effects of the first and secondtherapeutic agents.

In another aspect, the present invention provides a method of treatment,which comprises administering to a subject in need of such treatment acombination of a first therapeutic agent and a second therapeutic agent,the method comprising: (i) administering to the subject the firsttherapeutic agent including compound (1):

or a pharmaceutically acceptable salt thereof; (ii) monitoring level ofcompound (1) or a pharmaceutically acceptable salt thereof or ametabolite thereof in the subject using pharmacokinetic profiling; and(iii) administering the second therapeutic agent conditional on thelevel of the first therapeutic agent in the subject.

In another aspect, the present invention provides a method of treatment,which comprises administering to a subject in need of such treatment acombination of a first therapeutic agent and a second therapeutic agent,the method comprising: (i) administering to the subject the firsttherapeutic agent including compound (1):

or a pharmaceutically acceptable salt thereof; and (iii) administeringthe second therapeutic agent conditional on the expected half life ofexemplary compound (1) of about 3 hours to about 8 hours in the subjectundergoing treatment. In some embodiments, the expected half life ofexemplary compound (1) is from about 3 hours to about 24 hours in thesubject undergoing treatment.

In another aspect, the present invention provides a method of treatment,which comprises administering to a subject in need of such treatment acombination of a first therapeutic agent and a second therapeutic agent,the method comprising: (i) administering to the subject the firsttherapeutic agent including compound (1):

or a pharmaceutically acceptable salt thereof; and (iii) administeringthe second therapeutic agent conditional on adverse events from thefirst therapeutic agent have resolved or are resolving. In someembodiments, adverse events from the first therapeutic agent are relatedto the blood levels of the the first therapeutic agent or metabolitesthereof in the subject undergoing treatment.

In another aspect, the present invention provides a kit for monitoringof compound (1) or a pharmaceutically acceptable salt thereof or ametabolite thereof in an individual treated with compound (1) or apharmaceutically acceptable salt thereof or a metabolite thereof usingpharmacokinetic profiling, the kit comprising a plurality ofpoint-of-care device or a point of use device capable of quantitatingthe drug in the at least two samples or matrices suitable for storage ofthe at least two samples prior to quantitation by a laboratory. In someembodiments, a kit according to the present invention further comprisinginstructions for collecting and/or storing the at least two samples.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofembodiments of the present invention, will be better understood whenread in conjunction with the appended drawings of an exemplaryembodiment. It should be understood, however, that the invention is notlimited to the precise arrangements and instrumentalities shown.

In the drawings:

FIG. 1 illustrates a dose response relation showing effects of variousconcentrations of an exemplary compound of the present invention,compound (1), on viability of tumor and normal cells; and

FIG. 2 illustrates cell viability assay in human fetal lung fibroblast(MRC-5) cells following 72 hour treatment with an exemplary compound ofthe present invention, compound (1).

DETAILED DESCRIPTION OF THE INVENTION

Scientific and technical terms used herein are intended to have themeanings commonly understood by those of ordinary skill in the art. Suchterms are found defined and used in context in various standardreferences illustratively including J. Sambrook and D. W. Russell,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor LaboratoryPress; 3rd Ed., 2001; F. M. Ausubel, Ed., Short Protocols in MolecularBiology, Current Protocols; 5th Ed., 2002; B. Alberts et al., MolecularBiology of the Cell, 4th Ed., Garland, 2002; D. L. Nelson and M. M. Cox,Lehninger Principles of Biochemistry, 4th Ed., W.H. Freeman & Company,2004; Engelke, D. R., RNA Interference (RNAi): Nuts and Bolts of RNAiTechnology, DNA Press LLC, Eagleville, Pa., 2003; Herdewijn, P. (Ed.),Oligonucleotide Synthesis: Methods and Applications, Methods inMolecular Biology, Humana Press, 2004; A. Nagy, M. Gertsenstein, K.Vintersten, R. Behringer, Manipulating the Mouse Embryo: A LaboratoryManual, 3rd edition, Cold Spring Harbor Laboratory Press; Dec. 15, 2002,ISBN-10: 0879695919; Kursad Turksen (Ed.), Embryonic stem cells: methodsand protocols in Methods Mol Biol. 2002; 185, Humana Press; CurrentProtocols in Stem Cell Biology, ISBN: 9780470151808, as well as U.S.Patent Application Publication No. 20120276088. The content of each ofthe foregoing references is hereby incorporated by reference in itsentirety.

The singular terms “a,” “an,” and “the” are not intended to be limitingand include plural referents unless explicitly state or the contextclearly indicates otherwise.

I. COMPOSITIONS

In one aspect, the present invention provides a pharmaceuticalcomposition, comprising a compound (1):

or a pharmaceutically acceptable salt thereof. In one embodiment, thepharmaceutical composition comprises compound (1) or a pharmaceuticallyacceptable mono-salt thereof. In one embodiment, the pharmaceuticalcomposition comprises compound (1) or a pharmaceutically acceptabledi-salt thereof. In one embodiment, the pharmaceutical compositioncomprises compound (1) or a pharmaceutically acceptable mono- ormulti-salt (e.g., di-salt or tri-salt, where it is understood thatthroughout this disclosure a di-salt encompasses a multi-salt ortri-salt) thereof selected from the group consisting of hydrochloride,hydrobromide, hydrogensulphate, sulfates, phosphates, fumarates,succinates, oxalates and lactates, bisulfates, hydroxyl, tartrate,nitrate, citrate, bitartrate, carbonate, malate, maleate, fumaratesulfonate, methylsulfonate, formate, and carboxylate. In one embodiment,the pharmaceutical composition comprises compound (1) or apharmaceutically acceptable salt thereof selected from the groupconsisting of p-toluene-sulfonate, benzenesulfonate, methanesulfonate,oxalate, succinate, tartrate, citrate, fumarate and maleate. In oneembodiment, the pharmaceutical composition comprises compound (1) or apharmaceutically acceptable salt selected from the group consisting ofammonium, sodium, potassium, calcium, magnesium, zinc, lithium, and/orwith counter-ions such as methylamino, dimethylamino, diethylamino andtriethylamino counter-ions. In one embodiment, the pharmaceuticalcomposition comprises compound (1), a hydrochloride di-salt thereof(e.g., di-hydrochloride salt) or a hydrobromide di-salt thereof (e.g.,di-hydrobromide salt).

Compound (1) has the same chemical structure that would be revealed bystructural analysis (e.g. NMR, X-ray diffraction) of compound NSC350625, available from the National Cancer Institute's DevelopmentalTherapeutics Program Repository.

In one embodiment, a pharmaceutical composition in accordance with thepresent invention includes a di-salt (e.g., a di-hydrochloride salt) ofcompound (1).

Salts (e.g., di-salts or tri-salts) of compound (1) can be prepared fromcompound (1):

which can be obtained commercially or synthesized using standardchemical synthetic methodology known to one of ordinary skill in theart.

In one embodiment, the pharmaceutical composition in accordance with thepresent invention includes at least one pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers, included, butare not limited to, those found in Handbook of PharmaceuticalExcipients, 7th Edition, edited by Raymond C. Rowe et al., AmericanPharmaceutical Association, Washington, USA and Pharmaceutical Press,London; and earlier editions.

Exemplary pharmaceutically acceptable carriers, methods for makingpharmaceutical compositions and various dosage forms, as well as modesof administration are well-known in the art, for example as detailed inPharmaceutical Dosage Forms: Tablets, edited by Larry L. Augsburger andStephen W. Hoag., London: Informa Healthcare, 2008; and in L. V. Allen,Jr. et al., Ansel's Pharmaceutical Dosage Forms and Drug DeliverySystems, 8th Ed., Philadelphia, Pa.: Lippincott, Williams & Wilkins,2004; A. R. Gennaro, Remington: The Science and Practice of Pharmacy,Lippincott Williams & Wilkins, 21st ed., 2005, particularly chapter 89;and J. G. Hardman et al., Goodman & Gilman's The Pharmacological Basisof Therapeutics, McGraw-Hill Professional, 10th ed., 2001.

In some embodiments, the pharmaceutical composition of the presentinvention is formulated for ocular administration. In some embodiments,pharmaceutical compositions of the present invention are formulated fortopical ocular administration. In some embodiments, the pharmaceuticalcompositions are formulated as ointments, drops, or liquids. In someembodiments, the pharmaceutical composition of the present invention caninclude conventional pharmaceutical carriers such as aqueous, powdery oroily bases, thickeners or the like.

In some embodiments, the pharmaceutical composition of the presentinvention is formulated as intravenous formulation. In one embodiment,the intravenous formulation comprises compound (1) or a pharmaceuticallyacceptable salt of compound (1) dissolved in a solvent. In oneembodiment, the solvent comprises water. In one such embodiment, theintravenous formulation comprises compound (1) or a pharmaceuticallyacceptable salt of compound (1) dissolved in water at a concentration of25 mg/ml. In some embodiments, the intravenous formulation includes ahigher or a lower concentration of compound (1) or a pharmaceuticallyacceptable salt thereof. In one embodiment, the intravenous formulationincludes compound (1) or a pharmaceutically acceptable salt thereof in aconcentration of from about 5 mg/ml to about 100 mg/ml. In oneembodiment, the intravenous formulation includes compound (1) or apharmaceutically acceptable salt thereof in a concentration of about 50mg/ml. In one embodiment, the intravenous formulation includes compound(1) or a pharmaceutically acceptable salt thereof in a concentration ofabout 5 mg/ml. In one embodiment, the intravenous formulation includesfrom about 0.5% to about 10% of compound (1) or a pharmaceuticallyacceptable salt thereof. In one embodiment, the intravenous formulationincludes from about 5% of compound (1) or a pharmaceutically acceptablesalt thereof.

In some embodiments, the intravenous formulation has pH of about 3. Inone embodiment, pH of the intravenous formulation is adjusted to pH 3with a phosphate buffer. In some embodiments, the intravenousformulation includes dextrose or sodium chloride. In one embodiment, theintravenous formulation including compound (1) or a pharmaceuticallyacceptable salt thereof in a concentration of about 5 mg/ml and pH 3forms a stable solution. In one embodiment, the intravenous formulationincludes compound (1) or a pharmaceutically acceptable salt thereof in aconcentration of about 5 mg/ml and pH<5 and forms a stable solution. Inone embodiment, the intravenous formulation includes compound (1) or apharmaceutically acceptable salt thereof and one or more antioxidants.In one embodiment, the intravenous formulation includes a mixture ofmono- and di-hydrochloride salt of compound (1). In one embodiment, theintravenous formulation includes compound (1) or a pharmaceuticallyacceptable salt thereof as a 1% solution having compound (1) or tor apharmaceutically acceptable salt thereof in a concentration of about 10mg/ml. In one such embodiment, the intravenous formulation is a solutionhaving a pH of about 3.3. In one embodiment, the pH is less than 4.0.

In one embodiment, a pharmaceutical composition according to theinvention comprises about 0.1-99% of a salt of compound (1) or apharmaceutically acceptable salt thereof. In one such embodiment, thepharmaceutical composition further includes a pharmaceuticallyacceptable carrier. In one embodiment, a suitable pharmaceuticallyacceptable carrier includes an oil. In one embodiment, a suitablepharmaceutically acceptable carrier includes a sterile water. In oneembodiment, a suitable pharmaceutically acceptable carrier includes anaqueous carrier.

In some embodiments, the intravenous formulation includes dextroseand/or sodium.

In one embodiment, the intravenous formulation comprises compound (1) ora di-hydrochloride salt of compound (1) dissolved in water at 25 mg/ml.In one such embodiment, the intravenous formulation is adjusted to pH 3with phosphate buffer. In one such embodiment, the intravenousformulation includes dextrose or sodium chloride. In one suchembodiment, the intravenous formulation includes a higher or a lowerincrease or decrease the concentration of the di-hydrochloride salt ofcompound (1). In one embodiment, the intravenous formulation includescompound (1) or a di-hydrochloride salt of compound (1) in aconcentration of about 5 mg/ml. In one embodiment, the intravenousformulation including compound (1) or a di-hydrochloride salt ofcompound (1) in a concentration of about 5 mg/ml and pH 3 forms a stablesolution. In one embodiment, the intravenous formulation includescompound (1) or a di-hydrochloride salt of compound (1) in aconcentration of about 5 mg/ml and pH<5 and forms a stable solution. Inone embodiment, the intravenous formulation includes compound (1) or adi-hydrochloride salt of compound (1) and one or more antioxidants. Inone embodiment, the intravenous formulation includes a mixture of mono-and di-hydrochloride salt of compound (1). In one embodiment, theintravenous formulation includes compound (1) or a di-hydrochloride saltof compound (1) as a 1% solution having compound (1) or thedi-hydrochloride salt of compound (1) in a concentration of about 10mg/ml. In one such embodiment, the intravenous formulation is a solutionhaving a pH of about 3.33. In one embodiment, the pH is less than 4.0.

In one embodiment, the intravenous formulation includes from about 0.5%to about 10% (or from about 5 mg/ml to about 100 mg/ml) of compound (1)or a di-salt of compound (1). In one embodiment, the intravenousformulation includes from about 5% (or about 50 mg/ml) of compound (1)or a di-salt of compound (1). In one embodiment, the intravenousinfusion rate may be slowed to decrease side effects of compound (1) ora di-salt of compound (1).

In one embodiment, a pharmaceutical composition according to theinvention comprises about 0.1-99% of a salt of compound (1); and apharmaceutically acceptable carrier, e.g., an oil or a sterile water orother aqueous carriers. In one embodiment, a pharmaceutical compositionaccording to the invention comprises a mono or di-salt of compound (1)in a range of from about 5% to about 50% for oral dosage forms.

In some embodiments, a pharmaceutical composition of the presentinvention includes an antioxidant. Suitable antioxidants include:ascorbic acid derivatives such as ascorbic acid, erythorbic acid, sodiumascorbate, thiol derivatives such as thioglycerol, cysteine,acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione,tocopherols, butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), sulfurous acid salts such as sodium sulfate, sodium bisulfite,acetone sodium bisulfite, sodium metabisulfite, sodium sulfite, sodiumformaldehyde sulfoxylate, and sodium thiosulfate, nordihydroguaiareticacid. It should be noted that antioxidants used for aqueous formulationstypically include: sodium sulphite, sodium metabisulphite, sodiumformaldehyde sulphoxylate and ascorbic acid and combinations thereof,whereas antioxidants used in oil-based solutions, organic solvents,include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA)and propyl gallate and combinations thereof. In yet other embodiments,an antioxidant can be one or more of a flavanoid, an isoflavone,monothioglycerol, L-cysteine, thioglycolic acid, α-tocopherol, ascorbicacid 6-palmitate, dihydrolipoic acid, butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), vitamin E, propyl gallate, 0-carotene,ascorbic acid. Antioxidants can typically be used in about 0.1% to 1.0%by weight, more typically about 0.2%.

In one embodiment, the pharmaceutical composition includes compound (1)or a pharmaceutically acceptable salt thereof and at least one othertherapeutic agent. In one such embodiment, the at least one othertherapeutic agent is selected from the group consisting of hormoneanalogues and antihormones, aromatase inhibitors, LHRH agonists andantagonists, inhibitors of growth factors, growth factor antibodies,growth factor receptor antibodies, tyrosine kinase inhibitors;antimetabolites; antitumour antibiotics; platinum derivatives;alkylation agents; antimitotic agents; tubuline inhibitors; PARPinhibitors, topoisomerase inhibitors, serine/threonine kinaseinhibitors, tyrosine kinase inhibitors, protein interaction inhibitors,RAF inhibitors, MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbBreceptor inhibitors, rapamycin analogs, BTK inhibitors, CRM1 inhibitors(e.g., KPT185), P53 modulators (e.g., Nutlins), antiangiogenics (e.g.,axitinib, aflibercept, sorafenib, and regorafenib), amifostin,anagrelid, clodronat, filgrastin, interferon, interferon alpha,leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane,pamidronate and porfimer, 2-chlorodesoxyadenosine,2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine,131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,A 105972, A 204197, abiraterone, aldesleukin, alitretinoin,allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole,AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene,atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479(ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244(selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717,AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib),avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006,BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodardicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550,BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 (afatinib, tomtovok), BIBF 1120 (vargatef), BI 836845, BI 2536, BI6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid,bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib,brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCell,calcitriol, canertinib, canfosfamide, capecitabine,carboxyphthalatoplatin, CC1-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin,CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatinA4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine,deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010,E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFRinhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin,epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3,ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate,exemestane, exisulind, fenretinide, figitumumab, floxuridine, folicacid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fotemustine, galarubicin,gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide,GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068,GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptidevaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436(dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183,GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine,histamine, homoharringtonine, hyaluronic acid, hydroxyurea,hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab,idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12(cixutumumab), immunol, indisulam, interferon alpha-2a, interferonalpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117,INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide,leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin,lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301,mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf ingadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar,neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin,N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage,oncoVEXGM-CSF, ormiplatin, ortataxel, OX44 antibodies, OSI-027, OSI-906(linsitinib), 4-1BB antibodies, oxantrazole, oestrogen, panitumumab,patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204,PD0325901, PD-1 antibodies, PEG-paclitaxel, albumin-stabilizedpaclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427,P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine,perillylalcohol, pertuzumab, PI3K inhibitors, PI3K/mTOR inhibitors,PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054,PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate,pixantrone, phenoxodiol 0, PKI166, plevitrexed, plicamycin, polyprenicacid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin,R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436,rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors,regorafenib, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440,rhizoxin, rhu-MAb, rinfabate, risedronate, rituximab, robatumumab,rofecoxib, RO-31-7453, RO-5126766, RO-5068760, RPR 109881A, rubidazone,rubitecan, R-flurbiprofen, RX-0201, S-9788, sabarubicin, SAHA,sargramostim, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668,SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897,SR-31747, SR-13668, SRL-172, sorafenib, spiroplatin, squalamine,suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103,tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere,taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene,testosterone, testosterone propionate, tesmilifene, tetraplatin,tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin,thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine,tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinicacid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine,triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin,valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1,WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281,XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474,ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronat,zosuquidar, and combinations thereof.

In one embodiment, the at least one other therapeutic agent comprisesone or more hormone analogues and/or antihormones are selected from thegroup consisting of tamoxifen, toremifene, raloxifene, fulvestrant,megestrol acetate, flutamide, nilutamide, bicalutamide,aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate,fludrocortisone, fluoxymesterone, medroxy-progesterone, octreotide, andcombinations thereof. In one embodiment, the at least one othertherapeutic agent comprises one or more LHRH agonists and/or antagonistsselected from the group consisting of goserelin acetate, luprolideacetate, triptorelin pamoate and combinations thereof and wherein theLHRH antagonists are selected from the group consisting of Degarelix,Cetrorelix, Abarelix, Ozarelix, Degarelix combinations thereof. In oneembodiment, the at least one other therapeutic agent comprises one ormore growth factor inhibitors selected from the group consisting ofinhibitors of: platelet derived growth factor (PDGF), fibroblast growthfactor (FGF), vascular endothelial growth factor (VEGF), epidermalgrowth factor (EGF), insuline-like growth factors (IGF), human epidermalgrowth factor (HER) and hepatocyte growth factor (HGF). In oneembodiment, the at least one other therapeutic agent comprises one ormore inhibitors of the human epidermal growth factor selected from thegroup consisting of HER2, HER3, and HER4. In one embodiment, the atleast one other therapeutic agent comprises one or more tyrosine kinaseinhibitors selected from the group consisting of cetuximab, gefitinib,imatinib, lapatinib and trastuzumab, and combinations thereof. In oneembodiment, the at least one other therapeutic agent comprises one ormore aromatase inhibitors selected from the group consisting ofanastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, andcombinations thereof. In one embodiment, the at least one othertherapeutic agent comprises one or more antimetabolites which areantifolates selected from the group consisting of methotrexate,raltitrexed, and pyrimidine analogues. In one embodiment, the at leastone other therapeutic agent comprises one or more antimetabolites whichare pyrimidine analogues selected from the group consisting of5-fluorouracil, capecitabin and gemcitabin. In one embodiment, the atleast one other therapeutic agent comprises one or more antimetaboliteswhich are purine and/or adenosine analogues selected from the groupconsisting of mercaptopurine, thioguanine, cladribine and pentostatin,cytarabine, fludarabine, and combinations thereof. In one embodiment,the at least one other therapeutic agent comprises one or moreantitumour antibiotics selected from the group consisting ofanthracyclins, doxorubicin, daunorubicin, epirubicin and idarubicin,mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin andcombinations thereof. In one embodiment, the at least one othertherapeutic agent comprises one or more platinum derivatives selectedfrom the group consisting of cisplatin, oxaliplatin, carboplatin andcombinations thereof. In one embodiment, the at least one othertherapeutic agent comprises one or more alkylation agents selected fromthe group consisting of estramustin, meclorethamine, melphalan,chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide,temozolomide, nitrosoureas, and combinations thereof. In one embodiment,the at least one other therapeutic agent comprises nitrosoureas selectedfrom the group consisting of carmustin, lomustin, thiotepa, andcombinations thereof. In one embodiment, the at least one othertherapeutic agent comprises antimitotic agents selected from the groupconsisting of Vinca alkaloids and taxanes. In one embodiment, the atleast one other therapeutic agent comprises one or more taxanes selectedfrom the group consisting of paclitaxel, docetaxel, and combinationsthereof. In one embodiment, the at least one other therapeutic agentcomprises one or more Vinca alkaloids selected from the group consistingof vinblastine, vindesin, vinorelbin, vincristine, and combinationsthereof. In one embodiment, the at least one other therapeutic agentcomprises one or more topoisomerase inhibitors which areepipodophyllotoxins. In one embodiment, the at least one othertherapeutic agent comprises one or more epipodophyllotoxins selectedfrom the group consisting of etoposide and etopophos, teniposide,amsacrin, topotecan, irinotecan, mitoxantron, and combinations thereof.In one embodiment, the at least one other therapeutic agent comprisesone or more serine/threonine kinase inhibitors selected from the groupconsisting of PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors,mTORC1 inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, STK 33inhibitors, AKT inhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurorakinase inhibitors, and combinations thereof. In one embodiment, the atleast one other therapeutic agent comprises one or more tyrosine kinaseinhibitors which are PTK2/FAK inhibitors. In one embodiment, the atleast one other therapeutic agent comprises one or more protein proteininteraction inhibitors selected from the group consisting of IAP, Mcl-1,MDM2/MDMX and combinations thereof. In one embodiment, the at least oneother therapeutic agent comprises one or more rapamycin analogs selectedfrom the group consisting of everolimus, temsirolimus, ridaforolimus,sirolimus, and combinations thereof. In one embodiment, the at least oneother therapeutic agent comprises one or more therapeutic agentsselected from the group consisting of amifostin, anagrelid, clodronat,filgrastin, interferon, interferon alpha, leucovorin, rituximab,procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, andcombinations thereof. In one embodiment, the at least one othertherapeutic agent comprises one or more therapeutic agents selected fromthe group consisting of 2-chlorodesoxyadenosine,2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine,131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,A 105972, A 204197, abiraterone, aldesleukin, alitretinoin,allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole,AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene,atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479(ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244(selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717,AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib),avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006,BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodardicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550,BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 (afatinib, tomtovok), BIBF 1120 (vargatef), BI 836845, BI 2536, BI6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid,bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib,brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCell,calcitriol, canertinib, canfosfamide, capecitabine,carboxyphthalatoplatin, CC1-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin,CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatinA4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine,deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010,E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFRinhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin,epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3,ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate,exemestane, exisulind, fenretinide, figitumumab, floxuridine, folicacid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fotemustine, galarubicin,gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide,GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068,GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptidevaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436(dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183,GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine,histamine, homoharringtonine, hyaluronic acid, hydroxyurea,hydroxyprogesterone caproate, ibandronate, ibrutinib, ibritumomab,idatrexate, idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12(cixutumumab), immunol, indisulam, interferon alpha-2a, interferonalpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117,INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide,leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin,lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301,mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf ingadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar,neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin,N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage,oncoVEXGM-CSF, ormiplatin, ortataxel, OX44 antibodies, OSI-027, OSI-906(linsitinib), 4-1BB antibodies, oxantrazole, oestrogen, panitumumab,patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204,PD0325901, PD-1 antibodies, PEG-paclitaxel, albumin-stabilizedpaclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427,P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine,perillylalcohol, pertuzumab, PI3K inhibitors, PI3K/mTOR inhibitors,PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054,PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate,pixantrone, phenoxodiol 0, PKI166, plevitrexed, plicamycin, polyprenicacid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin,R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436,rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors,revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb,rinfabate, risedronate, rituximab, robatumumab, rofecoxib, RO-31-7453,RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan,R-flurbiprofen, RX-0201, S-9788, sabarubicin, SAHA, sargramostim,satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101,semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747,SR-13668, SRL-172, sorafenib, spiroplatin, squalamine,suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103,tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere,taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene,testosterone, testosterone propionate, tesmilifene, tetraplatin,tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin,thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine,tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinicacid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine,triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin,valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1,WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281,XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474,ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronat,zosuquidar, and combinations thereof.

In some embodiments, the at least one other therapeutic agent comprisesa steroid. Steroids include, but are not limited to, dexamethasone,prednisolone, methyl prednisolone, prednisone, hydrocortisone,triamcinolone, betamethasone, and cortivazol. In some embodiments, theat least one other therapeutic agent comprises an anti-emetic.Anti-emetics include, but are not limited to, 5-HT3 receptor agonists(such as dolasetron, granisetron, ondansetron, tropisetron,palonosetron, and mirtazapine), dopamine agonists (such as domperidone,olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine,alizapride, prochlorperazine, and metoclopramide), NK1 receptorantagonists (such as aprepitant and casopitant), antihistamines (such ascyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine,promethazine, hydroxyzine), cannabinoids (such as cannabis, dronabinol,nabilone, and sativex), benzodiazepines (such as midazolam andlorazepam), anticholinergics (such as hyoscine), trimethobenzamide,ginger, emetrol, propofol, peppermint, muscimol, and ajwain.

In some embodiments, the at least one other therapeutic agent comprisesanti-cancer agent which includes a mitotic inhibitor. In one embodiment,the mitotic inhibitor includes a taxane. In one embodiment, the mitoticinhibitor includes a taxane selected from the group consisting ofpaclitaxel and docetaxel.

In one embodiment, the pharmaceutical composition includes compound (1)or a pharmaceutically acceptable salt thereof and at least oneanti-cancer agent, wherein the anti-cancer agent includes, withoutlimitation, one or more of acivicin, aclarubicin, acodazole, acronine,adozelesin, aldesleukin, alitretinoin, allopurinol, altretamine,ambomycin, ametantrone, amifostine, aminoglutethimide, amsacrine,anastrozole, anthramycin, arsenic trioxide, asparaginase, asperlin,azacitidine, azetepa, azotomycin, batimastat, benzodepa, bevacizumab,bicalutamide, bisantrene, bisnafide dimesylate, bizelesin, bleomycin,brequinar, bropirimine, busulfan, cactinomycin, calusterone,capecitabine, caracemide, carbetimer, carboplatin, carmustine,carubicin, carzelesin, cedefingol, celecoxib, chlorambucil, cirolemycin,cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, daunorubicin, decitabine, dexormaplatin,dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin,droloxifene, dromostanolone, duazomycin, edatrexate, eflomithine,elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin,erbulozole, esorubicin, estramustine, etanidazole, etoposide, etoprine,fadrozole, fazarabine, fenretinide, floxuridine, fludarabine,fluorouracil, flurocitabine, fosquidone, fostriecin, fulvestrant,gemcitabine, hydroxyurea, idarubicin, ifosfamide, ilmofosine,interleukin II (IL-2, including recombinant interleukin II or rIL2),interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferonalfa-n3, interferon beta-Ia, interferon gamma-Ib, iproplatin,irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol,lomustine, losoxantrone, masoprocol, maytansine, mechlorethaminehydrochlride, megestrol, melengestrol acetate, melphalan, menogaril,mercaptopurine, methotrexate, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone, mycophenolic acid, nelarabine, nocodazole,nogalamycin, ormnaplatin, oxisuran, paclitaxel, pegaspargase,peliomycin, pentamustine, peplomycin, perfosfamide, pipobroman,piposulfan, piroxantrone hydrochloride, plicamycin, plomestane,porfimer, porfiromycin, prednimustine, procarbazine, puromycin,pyrazofurin, riboprine, rogletimide, safingol, semustine, simtrazene,sparfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin,streptonigrin, streptozocin, sulofenur, talisomycin, tamoxifen,tecogalan, tegafur, teloxantrone, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, topotecan, toremifene, trestolone, triciribine,trimetrexate, triptorelin, tubulozole, uracil mustard, uredepa,vapreotide, verteporfin, vinblastine, vincristine sulfate, vindesine,vinepidine, vinglycinate, vinleurosine, vinorelbine, vinrosidine,vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate, zorubicinand combinations thereof.

Examples of suitable anti-cancer agents include, but are not limited to,those described Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 12th Ed., edited by Laurence Brunton, Bruce Chabner, BjornKnollman, McGraw Hill Professional, 2010.

In some exemplary embodiments, the pharmaceutical composition includes asalt (e.g., a mono- or di-salt) of compound (1) and at least one othertherapeutic agent, wherein the at least one other therapeutic agentcomprises an anti-angiogenic agent. In one such embodiment, theanti-angiogenic agent is bevacizumab. In one embodiment, theanti-angiogenic agent is selected from the group consisting ofaflibercept, axitinib, angiostatin, endostatin, 16 kDa prolactinfragment, laminin peptides, fibronectin peptides, tissuemetalloproteinase inhibitors (TIMP 1, 2, 3, 4), plasminogen activator,inhibitors (PAI-1, -2), tumor necrosis factor α, (high dose, invitro),TGF-β1, interferons (IFN-α, -β, γ), ELR-CXC Chemokines: IL-12; SDF-1;MIG; platelet factor 4 (PF-4); IP-10, thrombospondin (TSP), SPARC,2-methoxyoestradiol, proliferin-related protein, suramin, sorafenib,regorafenib, thalidomide, cortisone, linomide, fumagillin (AGM-1470;TNP-470), tamoxifen, retinoids, CM101, dexamethasone, leukemiainhibitoryfactor (LIF), hedgehog inhibitor and combinations thereof.

The pharmaceutical combination in accordance with the present inventioncan include the first and second therapeutic agents in any desiredproportions provided that the synergistic or cooperative effect stilloccurs. The synergistic pharmaceutical combination in accordance withthe present invention preferably contains the first and secondtherapeutic agents in a ratio of from about 1:9 to about 9:1. In oneembodiment, the synergistic pharmaceutical combination pontains thefirst and second therapeutic agents in a ratio of from about 1:8 toabout 8:1. In one embodiment, the synergistic pharmaceutical combinationpontains the first and second therapeutic agents in a ratio of fromabout 1:7 to about 7:1. In one embodiment, the synergisticpharmaceutical combination pontains the first and second therapeuticagents in a ratio of from about 1:6 to about 6:1. In one embodiment, thesynergistic pharmaceutical combination pontains the first and secondtherapeutic agents in a ratio of from about 1:5 to about 5:1. In oneembodiment, the synergistic pharmaceutical combination pontains thefirst and second therapeutic agents in a ratio of from about 1:4 toabout 4:1. In one embodiment, the synergistic pharmaceutical combinationpontains the first and second therapeutic agents in a ratio of fromabout 1:3 to about 3:1. In one embodiment, the synergisticpharmaceutical combination pontains the first and second therapeuticagents in a ratio of from about 1:2 to about 2:1. In one embodiment, thesynergistic pharmaceutical combination pontains the first and secondtherapeutic agents in a ratio of approximately 1:1.

In some preferred embodiments, the second therapeutic agent is selectedfrom the group consisting of Allopurinol, Arsenic Trioxide, Azacitidine,Bortezomib, Bevacizumab, Capecitabine, Carboplatin, Celecoxib,Chlorambucil, Clofarabine, Cytarabine, Dacarbazine, Daunorubicin HCl,Docetaxel, Doxorubicin HCl, Floxuridine, Gemcitabine HCl, Hydroxyurea,Ifosfamide, Imatinib Mesylate, Ixabepilone, Lenalidomide, Megestrolacetate, Methotrexate, Mitotane, Mitoxantrone HCl, Oxaliplatin,Paclitaxel, Pralatrexate, Romidepsin, Sorafenib, Streptozocin, TamoxifenCitrate, Topotecan HCl, Tretinoin, Vandetanib, Vismodegib, Vorinostat,and combinations thereof.

In some prefered embodiments, the second therapeutic agent comprises asmall molecule multi-kinase inhibitor. In one embodiment, the smallmolecule multi-kinase inhibitor comprises sorafenib or regorafenib. Insome prefered embodiments, the second therapeutic agent comprises aHedgehog Pathway Inhibitor. In one prefered embodiment, the HedgehogPathway Inhibitor comprises vismodegib.

In some prefered embodiments, the second therapeutic agent includemembers of the classes drugs listed in the following table 1.

TABLE 1 Classes Of Drugs That Have Demonstrated Synergy Classes of drugsExamples Purine analogs Examples include, but are not limited to,allopurinol, oxypurinol, clofarabine, and tisopurine Pyrimidine analogsExamples include, but are not limited to, 5-fluorouracil, Floxuridine(FUDR), capecitabine, cytarabine, 6-azauracil (6-AU), and gemcitabine(Gemzar). Proteasome inhibitors Examples include, but are not limitedto, bortezomib, carfilzomib, cediranib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, ONCX 0912, CEP-18770, MLN9708, epoxomicin,and MG132. Anti-angiogenic Examples include, but are not limited to,bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, vandetanib,cabozantinib, axitinib, ponatinib, regorafenib, ranibizumab, lapatinib,and vandetanib. Platinum-based antineoplastic Examples include, but arenot limited to, cisplatin, drugs carboplatin, oxaliplatin, satraplatin,picoplatin, nedaplatin, and triplatin. COX-2 inhibitors Examplesinclude, but are not limited to, celecoxib, valdecoxib (Bextra),parecoxib (Dynastat), lumiracoxib, etoricoxib, and rofecoxib. Nitrogenmustards Examples include, but are not limited to, cyclophosphamide,chlorambucil, uramustine, ifosfamide, melphalan, bendamustine, andmustine. Alkylating agents Examples include, but are not limited to,cyclophosphamide, mechlorethamine or mustine (HN2) (trade nameMustardgen), uramustine or uracil mustard, melphalan, chlorambucil,ifosfamide, bendamustine, carmustine, lomustine, streptozocin, andbusulfan. Anthracyclines Examples include, but are not limited to,Daunorubicin (Daunomycin), Daunorubicin (liposomal), Doxorubicin(Adriamycin), Doxorubicin (liposomal), Epirubicin, Idarubicin,Valrubicin, and Mitoxantrone. Taxanes Examples include, but are notlimited to, Paclitaxel (Taxol), Docetaxel (Taxotere), and albumin-boundpaclitaxel (Abraxane). Nucleotide synthesis inhibitor Examples include,but are not limited to, methotrexate, pralatrexate, hydroxyurea, and5-fluorodeoxyuridine, 3,4- dihydroxybenzylamine. Bcr-abl inhibitorsExamples include, but are not limited to, imatinib, nilotinib,dasatinib, bosutinib and ponatinib. Other Examples include, but are notlimited to, arsenic trioxide, thalidomide, revlimid, and mitotane.Topoisomerase inhibitor Examples include, but are not limited to,amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin,Topotecan (Hycamtin), Irinotecan (CPT-11, Camptosar), Exatecan,Lurtotecan, ST 1481, CKD 602, ICRF-193, and genistein. HDAC inhibitorsExamples include, but are not limited to, Vorinostat (SAHA), Romidepsin(Istodax), Panobinostat (LBH589), Valproic acid (as Mg valproate),Belinostat (PXD101), Mocetinostat (MGCD0103), Abexinostat (PCI-24781),Entinostat (MS-275), SB939, Resminostat (4SC-201), Givinostat,Quisinostat (JNJ-26481585), CUDC-101, AR- 42, CHR-2845, CHR-3996,4SC-202, CG200745, ACY- 1215, ME-344, sulforaphane, Kevetrin, and ATRA.Multi-kinase inhibitors Examples include, but are not limited to,sorafenib, regorafenib, and vandetanib. Hormone therapies Examplesinclude, but are not limited to, tamoxifen, toremifene, Arimidex(anastrozole), Aromasin (exemestane), Femara (letrozole), andFulvestrant (Faslodex). Hedgehog signaling Inhibitors Examples include,but are not limited to, vismodegib, BMS-833923, IPI-926, LDE-225,PF-04449913, LEQ 506, and TAK-441.

In some embodiments, the second therapeutic agent includes drugs thattarget tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)receptors. In one embodiment, the second therapeutic agent includes arecombinant TRAIL or an agonistic antibody that activates one or moreTRAIL receptors. In one embodiment, the second therapeutic agentincludes one or more antibodies or recombinant TRAIL that activatesignaling by DR4 and/or DR5. In one embodiment, the second therapeuticagent includes one or more of mapatumumab, lexatumumab, Apomab, AMG-655,LBY-135 and rhApo2L/TRAIL. In one embodiment, the second therapeuticagent includes an active agent selected from the group consisting ofCamptothecin, 5-FU, capecitabine, cisplatin, doxorubicin, irinotecan,paclitaxel, cisplatin, bortezomib, BH3I-2, rituximab, radiation,triterpenoids, sorafenib, gemcitabine, HDAC inhibitors, carboplatin,T-101 (a gossypol derivate), ABT-263, ABT-737, and GX-15-070(obatoclax), vorinostat, cetuximab, panitumumab, bevacizumab, ganitumab,interferon gamma, sorafenib, XIAP antagonists, Bcl-2 antagonists, andSmac mimetics.

II. DOSE

In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose ranging from about 100 mg to about 2000 mg, where theweight can, in certain embodiments be based on compound (1) in its freebase form. In one embodiment, a pharmaceutical composition according tothe invention comprises compound (1) or a pharmaceutically acceptablesalt thereof in a dose ranging from about 40 mg to about 2000 mg, wherethe weight can, in certain embodiments be based on compound (1) in itsfree base form. In one embodiment, a pharmaceutical compositionaccording to the invention comprises compound (1) or a pharmaceuticallyacceptable salt thereof in a dose ranging from about 50 mg to about 2000mg, where the weight can, in certain embodiments be based on compound(1) in its free base form. In one embodiment, a pharmaceuticalcomposition according to the invention comprises compound (1) or apharmaceutically acceptable salt thereof in a dose ranging from about 60mg to about 2000 mg, where the weight can, in certain embodiments bebased on compound (1) in its free base form. In one embodiment, apharmaceutical composition according to the invention comprises compound(1) or a pharmaceutically acceptable salt thereof in a dose levelselected from the group consisting of from about 50 mg to about 200 mg,from about 50 mg to about 300 mg, from about 50 mg to about 400 mg, fromabout 50 mg to about 500 mg, from about 50 mg to about 600 mg, fromabout 50 mg to about 700 mg, from about 50 mg to about 800 mg, fromabout 50 mg to about 900 mg, from about 50 mg to about 1000 mg, fromabout 50 mg to about 1100 mg, from about 50 mg to about 1200 mg, fromabout 50 mg to about 1300 mg, from about 50 mg to about 1400 mg, fromabout 50 mg to about 1500 mg, from about 50 mg to about 1600 mg, fromabout 50 mg to about 1700 mg, from about 50 mg to about 1800 mg, andfrom about 50 mg to about 1900 mg, from 40 mg to 2000 mg. In oneembodiment, a pharmaceutical composition according to the inventioncomprises compound (1) or a pharmaceutically acceptable salt thereof ina dose level selected from the group consisting of from about 40 mg toabout 200 mg, from about 40 mg to about 300 mg, from about 40 mg toabout 400 mg, from about 40 mg to about 500 mg, from about 40 mg toabout 600 mg, from about 40 mg to about 700 mg, from about 40 mg toabout 800 mg, from about 40 mg to about 900 mg, from about 40 mg toabout 1000 mg, from about 40 mg to about 1100 mg, from about 40 mg toabout 1200 mg, from about 40 mg to about 1300 mg, from about 40 mg toabout 1400 mg, from about 40 mg to about 1500 mg, from about 40 mg toabout 1600 mg, from about 40 mg to about 1700 mg, from about 40 mg toabout 1800 mg, and from about 40 mg to about 1900 mg, from 40 mg to 2000mg. In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level selected from the group consisting of from about60 mg to about 200 mg, from about 60 mg to about 300 mg, from about 60mg to about 400 mg, from about 60 mg to about 500 mg, from about 60 mgto about 600 mg, from about 60 mg to about 700 mg, from about 60 mg toabout 800 mg, from about 60 mg to about 900 mg, from about 60 mg toabout 1000 mg, from about 60 mg to about 1100 mg, from about 60 mg toabout 1200 mg, from about 60 mg to about 1300 mg, from about 60 mg toabout 1400 mg, from about 60 mg to about 1500 mg, from about 60 mg toabout 1600 mg, from about 60 mg to about 1700 mg, from about 60 mg toabout 1800 mg, and from about 60 mg to about 1900 mg, from 60 mg to 2000mg. In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level selected from the group consisting of from about100 mg to about 200 mg, from about 100 mg to about 300 mg, from about100 mg to about 400 mg, from about 100 mg to about 500 mg, from about100 mg to about 600 mg, from about 100 mg to about 700 mg, from about100 mg to about 800 mg, from about 100 mg to about 900 mg, from about100 mg to about 1000 mg, from about 100 mg to about 1100 mg, from about100 mg to about 1200 mg, from about 100 mg to about 1300 mg, from about100 mg to about 1400 mg, from about 100 mg to about 1500 mg, from about100 mg to about 1600 mg, from about 100 mg to about 1700 mg, from about100 mg to about 1800 mg, and from about 100 mg to about 1900 mg, from 50mg to 2000 mg and from 40 mg to 200 mg. In one embodiment, apharmaceutical composition according to the invention comprises compound(1) or a pharmaceutically acceptable salt thereof in a dose levelselected from the group consisting of from about 200 mg to about 300 mg,from about 200 mg to about 400 mg, from about 200 mg to about 500 mg,from about 200 mg to about 600 mg, from about 200 mg to about 700 mg,from about 200 mg to about 800 mg, from about 200 mg to about 900 mg,from about 200 mg to about 1000 mg, from about 200 mg to about 1100 mg,from about 200 mg to about 1200 mg, from about 200 mg to about 1300 mg,from about 200 mg to about 1400 mg, from about 200 mg to about 1500 mg,from about 200 mg to about 1600 mg, from about 200 mg to about 1700 mg,from about 200 mg to about 1800 mg, and from about 200 mg to about 1900mg based on compound (1) in its free base form. In one embodiment, apharmaceutical composition according to the invention comprises compound(1) or a pharmaceutically acceptable salt thereof in a dose levelselected from the group consisting of from about 400 mg to about 500 mg,from about 400 mg to about 600 mg, from about 400 mg to about 700 mg,from about 400 mg to about 800 mg, from about 400 mg to about 900 mg,from about 400 mg to about 1000 mg, from about 400 mg to about 1100 mg,from about 400 mg to about 1200 mg, from about 400 mg to about 1300 mg,from about 400 mg to about 1400 mg, from about 400 mg to about 1500 mg,from about 400 mg to about 1600 mg, from about 400 mg to about 1700 mg,from about 400 mg to about 1800 mg, and from about 400 mg to about 1900mg based on compound (1) in its free base form. In one embodiment, apharmaceutical composition according to the invention comprises compound(1) or a pharmaceutically acceptable salt thereof in a dose levelselected from the group consisting of from about 50 mg to about 60 mg,from about 50 mg to about 70 mg, from about 50 mg to about 80 mg, fromabout 50 mg to about 90 mg, from about 50 mg to about 100 mg, from about60 mg to about 70 mg, from about 60 mg to about 80 mg, from about 60 mgto about 90 mg, from about 60 mg to about 100 mg, from about 70 mg toabout 80 mg, from about 70 mg to about 90 mg, from about 70 mg to about100 mg, from about 80 mg to about 90 mg, from about 80 mg to about 100mg, and from about 90 mg to about 100 mg

In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose ranging from about 1 mg/kg to about 40 mg/kg. In oneembodiment, a pharmaceutical composition according to the inventioncomprises compound (1) or a pharmaceutically acceptable salt thereof ina dose level selected from the group consisting of from about 1 mg/Kg toabout 40 mg/Kg, from about 2 mg/Kg to about 40 mg/Kg, from about 3 mg/Kgto about 40 mg/Kg, from about 4 mg/Kg to about 40 mg/Kg, from about 5mg/Kg to about 40 mg/Kg, from about 6 mg/Kg to about 40 mg/Kg, fromabout 7 mg/Kg to about 40 mg/Kg, from about 8 mg/Kg to about 40 mg/Kg,from about 9 mg/Kg to about 40 mg/Kg, from about 10 mg/Kg to about 40mg/Kg, from about 11 mg/Kg to about 40 mg/Kg, from about 12 mg/Kg toabout 40 mg/Kg, from about 13 mg/Kg to about 40 mg/Kg, from about 14mg/Kg to about 40 mg/Kg, from about 15 mg/Kg to about 40 mg/Kg, fromabout 16 mg/Kg to about 40 mg/Kg, from about 17 mg/Kg to about 40 mg/Kg,from about 18 mg/Kg to about 40 mg/Kg, from about 19 mg/Kg to about 40mg/Kg, from about 20 mg/Kg to about 40 mg/Kg, from about 21 mg/Kg toabout 40 mg/Kg, from about 22 mg/Kg to about 40 mg/Kg, from about 23mg/Kg to about 40 mg/Kg, from about 24 mg/Kg to about 40 mg/Kg, fromabout 25 mg/Kg to about 40 mg/Kg, from about 26 mg/Kg to about 40 mg/Kg,from about 27 mg/Kg to about 40 mg/Kg, from about 28 mg/Kg to about 40mg/Kg, from about 29 mg/Kg to about 40 mg/Kg, from about 30 mg/Kg toabout 40 mg/Kg, from about 31 mg/Kg to about 40 mg/Kg, from about 32mg/Kg to about 40 mg/Kg, from about 33 mg/Kg to about 40 mg/Kg, fromabout 34 mg/Kg to about 40 mg/Kg, from about 35 mg/Kg to about 40 mg/Kg,from about 36 mg/Kg to about 40 mg/Kg, from about 37 mg/Kg to about 40mg/Kg, from about 38 mg/Kg to about 40 mg/Kg, and from about 39 mg/Kg toabout 40 mg/Kg.

In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level selected from the group consisting of from about1 mg/Kg to about 30 mg/Kg, from about 2 mg/Kg to about 30 mg/Kg, fromabout 3 mg/Kg to about 30 mg/Kg, from about 4 mg/Kg to about 30 mg/Kg,from about 5 mg/Kg to about 30 mg/Kg, from about 6 mg/Kg to about 30mg/Kg, from about 7 mg/Kg to about 30 mg/Kg, from about 8 mg/Kg to about30 mg/Kg, from about 9 mg/Kg to about 30 mg/Kg, from about 10 mg/Kg toabout 30 mg/Kg, from about 11 mg/Kg to about 30 mg/Kg, from about 12mg/Kg to about 30 mg/Kg, from about 13 mg/Kg to about 30 mg/Kg, fromabout 14 mg/Kg to about 30 mg/Kg, from about 15 mg/Kg to about 30 mg/Kg,from about 16 mg/Kg to about 30 mg/Kg, from about 17 mg/Kg to about 30mg/Kg, from about 18 mg/Kg to about 30 mg/Kg, from about 19 mg/Kg toabout 30 mg/Kg, from about 20 mg/Kg to about 30 mg/Kg, from about 21mg/Kg to about 30 mg/Kg, from about 22 mg/Kg to about 30 mg/Kg, fromabout 23 mg/Kg to about 30 mg/Kg, from about 24 mg/Kg to about 30 mg/Kg,from about 25 mg/Kg to about 30 mg/Kg, from about 26 mg/Kg to about 30mg/Kg, from about 27 mg/Kg to about 30 mg/Kg, from about 28 mg/Kg toabout 30 mg/Kg, and from about 29 mg/Kg to about 30 mg/Kg.

In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level selected from the group consisting of from about1 mg/Kg to about 20 mg/Kg, from about 2 mg/Kg to about 20 mg/Kg, fromabout 3 mg/Kg to about 20 mg/Kg, from about 4 mg/Kg to about 20 mg/Kg,from about 5 mg/Kg to about 20 mg/Kg, from about 6 mg/Kg to about 20mg/Kg, from about 7 mg/Kg to about 20 mg/Kg, from about 8 mg/Kg to about20 mg/Kg, from about 9 mg/Kg to about 20 mg/Kg, from about 10 mg/Kg toabout 20 mg/Kg, from about 11 mg/Kg to about 20 mg/Kg, from about 12mg/Kg to about 20 mg/Kg, from about 13 mg/Kg to about 20 mg/Kg, fromabout 14 mg/Kg to about 20 mg/Kg, from about 15 mg/Kg to about 20 mg/Kg,from about 16 mg/Kg to about 20 mg/Kg, from about 17 mg/Kg to about 20mg/Kg, from about 18 mg/Kg to about 20 mg/Kg, and from about 19 mg/Kg toabout 20 mg/Kg.

In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level selected from the group consisting of from about1 mg/Kg to about 10 mg/Kg, from about 2 mg/Kg to about 10 mg/Kg, fromabout 3 mg/Kg to about 10 mg/Kg, from about 4 mg/Kg to about 10 mg/Kg,from about 5 mg/Kg to about 10 mg/Kg, from about 6 mg/Kg to about 10mg/Kg, from about 7 mg/Kg to about 10 mg/Kg, from about 8 mg/Kg to about10 mg/Kg, and from about 9 mg/Kg to about 10 mg/Kg.

In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level ranging from about 37.5 mg/m² to about 1500mg/m². In one embodiment, a pharmaceutical composition according to theinvention comprises compound (1) or a pharmaceutically acceptable saltthereof in a dose level selected from the group consisting of from aboutfrom about 40 mg/m² to about 1500 mg/m², from about 45 mg/m² to about1500 mg/m², from about 50 mg/m² to about 1500 mg/m², from about 55 mg/m²to about 1500 mg/m², from about 60 mg/m² to about 1500 mg/m², from about65 mg/m² to about 1500 mg/m², from about 70 mg/m² to about 1500 mg/m²,from about 75 mg/m² to about 1500 mg/m², from about 80 mg/m² to about1500 mg/m², from about 85 mg/m² to about 1500 mg/m², from about 90 mg/m²to about 1500 mg/m², from about 95 mg/m² to about 1500 mg/m², from about100 mg/m² to about 1500 mg/m², from about 105 mg/m² to about 1500 mg/m²,from about 110 mg/m² to about 1500 mg/m², from about 115 mg/m² to about1500 mg/m², from about 120 mg/m² to about 1500 mg/m², from about 125mg/m² to about 1500 mg/m², from about 130 mg/m² to about 1500 mg/m²,from about 135 mg/m² to about 1500 mg/m², from about 140 mg/m² to about1500 mg/m², from about 145 mg/m² to about 1500 mg/m², from about 150mg/m² to about 1500 mg/m², from about 155 mg/m² to about 1500 mg/m²,from about 160 mg/m² to about 1500 mg/m², from about 165 mg/m² to about1500 mg/m², from about 170 mg/m² to about 1500 mg/m², from about 175mg/m² to about 1500 mg/m², from about 180 mg/m² to about 1500 mg/m²,from about 185 mg/m² to about 1500 mg/m², from about 190 mg/m² to about1500 mg/m², from about 195 mg/m² to about 1500 mg/m², from about 200mg/m² to about 1500 mg/m², from about 205 mg/m² to about 1500 mg/m²,from about 210 mg/m² to about 1500 mg/m², from about 215 mg/m² to about1500 mg/m², from about 220 mg/m² to about 1500 mg/m², from about 225mg/m² to about 1500 mg/m², from about 230 mg/m² to about 1500 mg/m²,from about 235 mg/m² to about 1500 mg/m², from about 240 mg/m² to about1500 mg/m², from about 245 mg/m² to about 1500 mg/m², from about 250mg/m² to about 1500 mg/m², from about 255 mg/m² to about 1500 mg/m²,from about 260 mg/m² to about 1500 mg/m², from about 265 mg/m² to about1500 mg/m², from about 270 mg/m² to about 1500 mg/m², from about 275mg/m² to about 1500 mg/m², from about 280 mg/m² to about 1500 mg/m²,from about 285 mg/m² to about 1500 mg/m², from about 290 mg/m² to about1500 mg/m², from about 295 mg/m² to about 1500 mg/m², from about 300mg/m² to about 1500 mg/m², from about 305 mg/m² to about 1500 mg/m²,from about 310 mg/m² to about 1500 mg/m², from about 315 mg/m² to about1500 mg/m², from about 320 mg/m² to about 1500 mg/m², from about 325mg/m² to about 1500 mg/m², from about 330 mg/m² to about 1500 mg/m²,from about 335 mg/m² to about 1500 mg/m², from about 340 mg/m² to about1500 mg/m², from about 345 mg/m² to about 1500 mg/m², from about 350mg/m² to about 1500 mg/m², from about 355 mg/m² to about 1500 mg/m²,from about 360 mg/m² to about 1500 mg/m², from about 365 mg/m² to about1500 mg/m², from about 370 mg/m² to about 1500 mg/m², from about 375mg/m² to about 1500 mg/m², from about 380 mg/m² to about 1500 mg/m²,from about 385 mg/m² to about 1500 mg/m², from about 390 mg/m² to about1500 mg/m², from about 395 mg/m² to about 1500 mg/m², from about 400mg/m² to about 1500 mg/m², from about 405 mg/m² to about 1500 mg/m²,from about 410 mg/m² to about 1500 mg/m², from about 415 mg/m² to about1500 mg/m², from about 420 mg/m² to about 1500 mg/m², from about 425mg/m² to about 1500 mg/m², from about 430 mg/m² to about 1500 mg/m²,from about 435 mg/m² to about 1500 mg/m², from about 440 mg/m² to about1500 mg/m², from about 445 mg/m² to about 1500 mg/m², from about 450mg/m² to about 1500 mg/m², from about 455 mg/m² to about 1500 mg/m²,from about 460 mg/m² to about 1500 mg/m², from about 465 mg/m² to about1500 mg/m², from about 470 mg/m² to about 1500 mg/m², from about 475mg/m² to about 1500 mg/m², from about 480 mg/m² to about 1500 mg/m²,from about 485 mg/m² to about 1500 mg/m², from about 490 mg/m² to about1500 mg/m², from about 495 mg/m² to about 1500 mg/m², from about 500mg/m² to about 1500 mg/m², from about 505 mg/m² to about 1500 mg/m²,from about 510 mg/m² to about 1500 mg/m², from about 515 mg/m² to about1500 mg/m², from about 520 mg/m² to about 1500 mg/m², from about 525mg/m² to about 1500 mg/m², from about 530 mg/m² to about 1500 mg/m²,from about 535 mg/m² to about 1500 mg/m², from about 540 mg/m² to about1500 mg/m², from about 545 mg/m² to about 1500 mg/m², from about 550mg/m² to about 1500 mg/m², from about 555 mg/m² to about 1500 mg/m²,from about 560 mg/m² to about 1500 mg/m², from about 565 mg/m² to about1500 mg/m², from about 570 mg/m² to about 1500 mg/m², from about 575mg/m² to about 1500 mg/m², from about 580 mg/m² to about 1500 mg/m²,from about 585 mg/m² to about 1500 mg/m², from about 590 mg/m² to about1500 mg/m², from about 595 mg/m² to about 1500 mg/m², from about 600mg/m² to about 1500 mg/m², from about 605 mg/m² to about 1500 mg/m²,from about 610 mg/m² to about 1500 mg/m², from about 615 mg/m² to about1500 mg/m², from about 620 mg/m² to about 1500 mg/m², from about 625mg/m² to about 1500 mg/m², from about 630 mg/m² to about 1500 mg/m²,from about 635 mg/m² to about 1500 mg/m², from about 640 mg/m² to about1500 mg/m², from about 645 mg/m² to about 1500 mg/m², from about 650mg/m² to about 1500 mg/m², from about 655 mg/m² to about 1500 mg/m²,from about 660 mg/m² to about 1500 mg/m², from about 665 mg/m² to about1500 mg/m², from about 670 mg/m² to about 1500 mg/m², from about 675mg/m² to about 1500 mg/m², from about 680 mg/m² to about 1500 mg/m²,from about 685 mg/m² to about 1500 mg/m², from about 690 mg/m² to about1500 mg/m², from about 695 mg/m² to about 1500 mg/m², from about 700mg/m² to about 1500 mg/m², from about 705 mg/m² to about 1500 mg/m²,from about 710 mg/m² to about 1500 mg/m², from about 715 mg/m² to about1500 mg/m², from about 720 mg/m² to about 1500 mg/m², from about 725mg/m² to about 1500 mg/m², from about 730 mg/m² to about 1500 mg/m²,from about 735 mg/m² to about 1500 mg/m², from about 740 mg/m² to about1500 mg/m², from about 745 mg/m² to about 1500 mg/m², from about 750mg/m² to about 1500 mg/m², from about 755 mg/m² to about 1500 mg/m²,from about 760 mg/m² to about 1500 mg/m², from about 765 mg/m² to about1500 mg/m², from about 770 mg/m² to about 1500 mg/m², from about 775mg/m² to about 1500 mg/m², from about 780 mg/m² to about 1500 mg/m²,from about 785 mg/m² to about 1500 mg/m², from about 790 mg/m² to about1500 mg/m², from about 795 mg/m² to about 1500 mg/m², from about 800mg/m² to about 1500 mg/m², from about 805 mg/m² to about 1500 mg/m²,from about 810 mg/m² to about 1500 mg/m², from about 815 mg/m² to about1500 mg/m², from about 820 mg/m² to about 1500 mg/m², from about 825mg/m² to about 1500 mg/m², from about 830 mg/m² to about 1500 mg/m²,from about 835 mg/m² to about 1500 mg/m², from about 840 mg/m² to about1500 mg/m², from about 845 mg/m² to about 1500 mg/m², from about 850mg/m² to about 1500 mg/m², from about 855 mg/m² to about 1500 mg/m²,from about 860 mg/m² to about 1500 mg/m², from about 865 mg/m² to about1500 mg/m², from about 870 mg/m² to about 1500 mg/m², from about 875mg/m² to about 1500 mg/m², from about 880 mg/m² to about 1500 mg/m²,from about 885 mg/m² to about 1500 mg/m², from about 890 mg/m² to about1500 mg/m², from about 895 mg/m² to about 1500 mg/m², from about 900mg/m² to about 1500 mg/m², from about 905 mg/m² to about 1500 mg/m²,from about 910 mg/m² to about 1500 mg/m², from about 915 mg/m² to about1500 mg/m², from about 920 mg/m² to about 1500 mg/m², from about 925mg/m² to about 1500 mg/m², from about 930 mg/m² to about 1500 mg/m²,from about 935 mg/m² to about 1500 mg/m², from about 940 mg/m² to about1500 mg/m², from about 945 mg/m² to about 1500 mg/m², from about 950mg/m² to about 1500 mg/m², from about 955 mg/m² to about 1500 mg/m²,from about 960 mg/m² to about 1500 mg/m², from about 965 mg/m² to about1500 mg/m², from about 970 mg/m² to about 1500 mg/m², from about 975mg/m² to about 1500 mg/m², from about 980 mg/m² to about 1500 mg/m²,from about 985 mg/m² to about 1500 mg/m², from about 990 mg/m² to about1500 mg/m², from about 995 mg/m² to about 1500 mg/m², from about 1000mg/m² to about 1500 mg/m², from about 1005 mg/m² to about 1500 mg/m²,from about 1010 mg/m² to about 1500 mg/m², from about 1015 mg/m² toabout 1500 mg/m², from about 1020 mg/m² to about 1500 mg/m², from about1025 mg/m² to about 1500 mg/m², from about 1030 mg/m² to about 1500mg/m², from about 1035 mg/m² to about 1500 mg/m², from about 1040 mg/m²to about 1500 mg/m², from about 1045 mg/m² to about 1500 mg/m², fromabout 1050 mg/m² to about 1500 mg/m², from about 1055 mg/m² to about1500 mg/m², from about 1060 mg/m² to about 1500 mg/m², from about 1065mg/m² to about 1500 mg/m², from about 1070 mg/m² to about 1500 mg/m²,from about 1075 mg/m² to about 1500 mg/m², from about 1080 mg/m² toabout 1500 mg/m², from about 1085 mg/m² to about 1500 mg/m², from about1090 mg/m² to about 1500 mg/m², from about 1095 mg/m² to about 1500mg/m², from about 1100 mg/m² to about 1500 mg/m², from about 1105 mg/m²to about 1500 mg/m², from about 1110 mg/m² to about 1500 mg/m², fromabout 1115 mg/m² to about 1500 mg/m², from about 1120 mg/m² to about1500 mg/m², from about 1125 mg/m² to about 1500 mg/m², from about 1130mg/m² to about 1500 mg/m², from about 1135 mg/m² to about 1500 mg/m²,from about 1140 mg/m² to about 1500 mg/m², from about 1145 mg/m² toabout 1500 mg/m², from about 1150 mg/m² to about 1500 mg/m², from about1155 mg/m² to about 1500 mg/m², from about 1160 mg/m² to about 1500mg/m², from about 1165 mg/m² to about 1500 mg/m², from about 1170 mg/m²to about 1500 mg/m², from about 1175 mg/m² to about 1500 mg/m², fromabout 1180 mg/m² to about 1500 mg/m², from about 1185 mg/m² to about1500 mg/m², from about 1190 mg/m² to about 1500 mg/m², from about 1195mg/m² to about 1500 mg/m², from about 1200 mg/m² to about 1500 mg/m²,from about 1205 mg/m² to about 1500 mg/m², from about 1210 mg/m² toabout 1500 mg/m², from about 1215 mg/m² to about 1500 mg/m², from about1220 mg/m² to about 1500 mg/m², from about 1225 mg/m² to about 1500mg/m², from about 1230 mg/m² to about 1500 mg/m², from about 1235 mg/m²to about 1500 mg/m², from about 1240 mg/m² to about 1500 mg/m², fromabout 1245 mg/m² to about 1500 mg/m², from about 1250 mg/m² to about1500 mg/m², from about 1255 mg/m² to about 1500 mg/m², from about 1260mg/m² to about 1500 mg/m², from about 1265 mg/m² to about 1500 mg/m²,from about 1270 mg/m² to about 1500 mg/m², from about 1275 mg/m² toabout 1500 mg/m², from about 1280 mg/m² to about 1500 mg/m², from about1285 mg/m² to about 1500 mg/m², from about 1290 mg/m² to about 1500mg/m², from about 1295 mg/m² to about 1500 mg/m², from about 1300 mg/m²to about 1500 mg/m², from about 1305 mg/m² to about 1500 mg/m², fromabout 1310 mg/m² to about 1500 mg/m², from about 1315 mg/m² to about1500 mg/m², from about 1320 mg/m² to about 1500 mg/m², from about 1325mg/m² to about 1500 mg/m², from about 1330 mg/m² to about 1500 mg/m²,from about 1335 mg/m² to about 1500 mg/m², from about 1340 mg/m² toabout 1500 mg/m², from about 1345 mg/m² to about 1500 mg/m², from about1350 mg/m² to about 1500 mg/m², from about 1355 mg/m² to about 1500mg/m², from about 1360 mg/m² to about 1500 mg/m², from about 1365 mg/m²to about 1500 mg/m², from about 1370 mg/m² to about 1500 mg/m², fromabout 1375 mg/m² to about 1500 mg/m², from about 1380 mg/m² to about1500 mg/m², from about 1385 mg/m² to about 1500 mg/m², from about 1390mg/m² to about 1500 mg/m², from about 1395 mg/m² to about 1500 mg/m²,from about 1400 mg/m² to about 1500 mg/m², from about 1405 mg/m² toabout 1500 mg/m², from about 1410 mg/m² to about 1500 mg/m², from about1415 mg/m² to about 1500 mg/m², from about 1420 mg/m² to about 1500mg/m², from about 1425 mg/m² to about 1500 mg/m², from about 1430 mg/m²to about 1500 mg/m², from about 1435 mg/m² to about 1500 mg/m², fromabout 1440 mg/m² to about 1500 mg/m², from about 1445 mg/m² to about1500 mg/m², from about 1450 mg/m² to about 1500 mg/m², from about 1455mg/m² to about 1500 mg/m², from about 1460 mg/m² to about 1500 mg/m²,from about 1465 mg/m² to about 1500 mg/m², from about 1470 mg/m² toabout 1500 mg/m², from about 1475 mg/m² to about 1500 mg/m², from about1480 mg/m² to about 1500 mg/m², from about 1485 mg/m² to about 1500mg/m², from about 1490 mg/m² to about 1500 mg/m², and from about 1495mg/m² to about 1500 mg/m².

III. DOSAGE FORMS

Suitable pharmaceutical compositions for use with the methods of thepresent invention can be formulated into any dosage form that can beadministered to a patient. In one embodiment, the pharmaceuticalcomposition is in the form of an oral dosage unit or parenteral dosageunit. In one embodiment, the pharmaceutical composition is in the formof an oral dosage unit. In some embodiments, an oral dosage unit isfractionated into several, smaller doses, which are administered to asubject over a predetermined period of time in order to reduce toxicityof the therapeutic agent being administered. In some embodiments, anoral dosage unit is administered by a tablet or capsule comprising acontrolled release formulation that can include a plurality ofparticles, granules, pellets, minitablets or tablets. In one embodiment,the pharmaceutical composition is in the form of a parenteral dosageunit. In one embodiment, the pharmaceutical composition is in the formof a parenteral dosage unit, wherein the parenteral dosage unit isselected from the group consisting of intravenous (IV), subcutaneous(SC), and intramuscular (M), rectal (PR) and transdermal dosage units.In one embodiment, the pharmaceutical composition is in a dosage formselected from the group consisting of sterile solutions, suspensions,suppositories, tablets and capsules. In one embodiment, the compositionis an oral dosage form selected from the group consisting of a tablet,caplet, capsule, lozenge, syrup, liquid, suspension and elixir. In oneembodiment, the composition is in an oral dosage form selected from thegroup consisting of tablets, hard shell capsules, soft gelatin capsules,beads, granules, aggregates, powders, gels, solids and semi-solids.

In some embodiments, suitable forms of pharmaceutical compositions foruse in the methods of the present invention include dermatologicalcompositions adapted for cutaneous topical administration. In some suchembodiments, dermatological compositions include a cosmetically orpharmaceutically acceptable medium. In some embodiments, thedermatological compositions for topical administration can includeointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. In some embodiments, conventional pharmaceutical carriers,aqueous, powder or oily bases, thickeners, skin enhancers and the likecan be necessary or desirable and therefore can be used. Examples ofsuitable enhancers include, but are not limited to, ethers such asdiethylene glycol monoethyl ether (available commercially asTranscutol®) and diethylene glycol monomethyl ether; surfactants such assodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60,80), and lecithin (U.S. Pat. No. 4,783,450); alcohols such as ethanol,propanol, octanol, benzyl alcohol, and the like; polyethylene glycol andesters thereof such as polyethylene glycol monolaurate; amides and othernitrogenous compounds such as urea, dimethylacetamide (DMA),dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone,ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones;and organic acids, particularly citric acid and succinic acid. Azone®and sulfoxides such as DMSO and Cι0MSO may also be used, but are lesspreferred.

In some embodiments, the pharmaceutical composition of the presentinvention is in a dosage form selected from the group consisting ofsustained release forms, controlled release forms, delayed release formsand response release forms.

IV. METHODS OF USE

The compositions and methods of the present invention have utility intreating many disease conditions, including cancer (e.g., colorectal,brain, and glioblastoma). In one embodiment, the compositions andmethods of the present invention are used to treat diseases such asocular melanoma, desmoplastic round cell tumor, chondrosarcoma,leptomengial disease, diffuse large B-cell lymphoma, Acute LymphoblasticLeukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-RelatedCancers, AIDS-Related Lymphoma, Anal or Rectal Cancer, Appendix Cancer,Astrocytomas, and Atypical Teratoid/Rhabdoid Tumor. In one embodiment,the compositions and methods of the present invention are used to treatdiseases such as Basal Cell Carcinoma, Basal Cell Nevus Syndrome,Gorlin-Nevus Syndrome, Bile Duct Cancer, Bladder Cancer, Bone Cancer,Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Tumor, BreastCance, Bronchial Tumors, Burkitt Lymphoma, and Spinal Cord Tumors. Inone embodiment, the compositions and methods of the present inventionare used to treat cdiseases such as Carcinoid Tumor, Carcinoma ofUnknown Primary, Central Nervous System Atypical Teratoid/RhabdoidTumor, Leptomeningeal Disease, Central Nervous System Embryonal Tumors,Central Nervous System Lymphoma, Cervical Cancer, Chordoma, ChronicLymphocytic Leukemia, Chronic Myelogenous Leukemia, ChronicMyeloproliferative Disorders, Colon Cancer, Colorectal Cancer,Craniopharyngioma, and Cutaneous T-Cell Lymphoma (including, but notlimited to, Sezary syndrome and mycosis fungoides (MF)). In oneembodiment, the compositions and methods of the present invention areused to treat cdiseases such as Embryonal Tumors of Central NervousSystem, Endometrial Cancer, Ependymoblastoma, Ependymoma, EsophagealCancer, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, and EyeCancer. In one embodiment, the compositions and methods of the presentinvention are used to treat cdiseases such as Gallbladder Cancer,Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor,Gastrointestinal Stromal Tumor (GIST), Germ Cell Tumor, GestationalTrophoblastic Tumor, and Glioma. In one embodiment, the compositions andmethods of the present invention are used to treat cancer selected fromthe group consisting of Hairy Cell Leukemia, Head and Neck Cancer,Hepatocellular (Liver) Cancer, Histiocytosis, Hodgkin Lymphoma, andHypopharyngeal Cancer. In one embodiment, the compositions and methodsof the present invention are used to treat cdiseases such as KaposiSarcoma, and Kidney (Renal Cell) Cancer. In one embodiment, thecompositions and methods of the present invention are used to treatdiseases such as Langerhans Cell Histiocytosis, Laryngeal Cancer, Lipand Oral Cavity Cancer, Liver Cancer, Lung Cancer, Non-Hodgkin Lymphoma,and Primary Central Nervous System Lymphoma. In one embodiment, thecompositions and methods of the present invention are used to treatdiseases such as Waldenstrom's macroglobulinemia (lymphoplasmacyticlymphoma), Malignant Fibrous Histiocytoma of Bone and Osteosarcoma,Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma,Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary,Multiple Endocrine Neoplasia Syndrome, Mouth Cancer, MultipleMyeloma/Plasma Cell Neoplasm, Mycosis Fungoides, MyelodysplasticSyndromes, Myelodysplastic/Myeloproliferative Neoplasms, MultipleMyeloma, and Myeloproliferative Disorders. In one embodiment, thecompositions and methods of the present invention are used to treatcancer. In one embodiment, the compositions and methods of the presentinvention are used to treat diseases such as Nasal Cavity and ParanasalSinus Cancer, Nasopharyngeal Cancer, and Neuroblastoma. In oneembodiment, the compositions and methods of the present invention areused to treat diseases such as Oral Cancer, Lip and Oral Cavity Cancer,Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma ofBone, Ovarian Cancer, Ovarian Germ Cell Tumor, Ovarian EpithelialCancer, and Ovarian Low Malignant Potential Tumor. In one embodiment,the compositions and methods of the present invention are used to treatdiseases such as Pancreatic Cancer, Papillomatosis, Paranasal Sinus andNasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, PharyngealCancer, Pineal Parenchymal Tumors of Intermediate Differentiation,Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors,Pituitary Tumor, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer,Primary Central Nervous System Lymphoma, and Prostate Cancer. In oneembodiment, the compositions and methods of the present invention areused to treat cancer selected from the group consisting of RectalCancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, RespiratoryTract Carcinoma Involving the NUT Gene on Chromosome 15, Retinoblastoma,and Rhabdomyosarcoma. In one embodiment, the compositions and methods ofthe present invention are used to treat high grade prostate cancer. Inone embodiment, the compositions and methods of the present inventionare used to treat medium grade prostate cancer. In one embodiment, thecompositions and methods of the present invention are used to treat lowgrade prostate cancer. In one embodiment, the compositions and methodsof the present invention are used to treat castration-resistant prostatecancer.

In one embodiment, the compositions and methods of the present inventionare used to treat a proliferative skin disorder. In one embodiment, thecompositions and methods of the present invention are used to treat aproliferative skin disorder, wherein the proliferative skin disorder ispsoriasis. In one embodiment, the compositions and methods of thepresent invention are used to treat cancer selected from the groupconsisting of Salivary Gland Cancer, Sarcoma, Sezary Syndrome, SkinCancer, Ocular Cancer, Skin Carcinoma, Small Intestine Cancer, SoftTissue Sarcoma, Squamous Cell Carcinom, Squamous Neck Cancer with OccultPrimary, and Supratentorial Primitive Neuroectodermal Tumors. In oneembodiment, the compositions and methods of the present invention areused to treat cancer selected from the group consisting of T-CellLymphoma, Testicular Cancer, Throat Cancer, Thymoma and ThymicCarcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvisand Ureter, and Gestational Trophoblastic Tumor. In one embodiment, thecompositions and methods of the present invention are used to treatcancer selected from the group consisting of Carcinoma of UnknownPrimary Site, Cancer of Unknown Primary Site, Unusual Cancers ofChildhood, Transitional Cell Cancer Of the Renal Pelvis and Ureter,Urethral Cancer, and Uterine Sarcoma. In one embodiment, thecompositions and methods of the present invention are used to treatcancer selected from the group consisting of Vaginal Cancer, and VulvarCancer. In one embodiment, the compositions and methods of the presentinvention are used to treat cancer selected from the group consisting ofWilms Tumor, and Women's Cancers.

In some embodiments, the compositions and methods of the presentinvention are used as a first-line therapy (sometimes called primarytherapy). In some embodiments, the compositions and methods of thepresent invention are used as a second-line therapy. In someembodiments, the compositions and methods of the present invention areused as a third-line therapy. In some embodiments, the compositions andmethods of the present invention are used as a salvage therapy. The term“salvage therapy” as used herein means a therapeutic agent that can betaken with any regimen after a subject's initial treatment regimen hasfailed or after the subject's condition has not responded to an initialtreatment. In some embodiments, the compositions and methods of thepresent invention are used as a rescue therapy. In one embodiment of therescue therapy, the compositions of the present invention are used as arescue agent to counteract the action of an initial treatment. In oneembodiment of the rescue therapy, the compositions of the presentinvention are used as rescue agent which is administered to a subjectwho has developed resistance to a standard or an initial treatment. Insome embodiments, the compositions and methods of the present inventionare used as a neoadjuvant therapy. In one embodiment, the neoadjuvanttherapy comprises administration of one or more of the therapeuticagents of the present invention to a subject before a main or first linetreatment. In one embodiment, the neoadjuvant therapy reduces the sizeor extent of the cancer being treated before a main or first linetreatment is administered to the subject undergoing treatment. In someembodiments, the compositions and methods of the present invention areused as an adjuvant therapy. In one embodiment, the adjuvant therapycomprises administration of one or more therapeutic agents of thepresent invention to a subject, wherein the one or more therapeuticagent that modify the effect of other therapeutic agents that arealready administered to the subject or are concurrently administered tothe subject or subsequently administered to the subject.

In some embodiments, the compositions and methods of the presentinvention exhibit reduced chance of drug-drug interactions. In someembodiments, the compositions and methods of the present invention,compound (1) and/or a pharmaceutically acceptable salt thereof areeliminated from the patient's body before it can interact with anotherpharmaceutically active agent.

In some embodiments, the compositions and methods of the presentinvention, compound (1) and/or a pharmaceutically acceptable saltthereof exhibit tonicity level that facilitates combinations with otherpharmaceutical agents.

The utility of the methods and compositions of the present invention isnot limited to any particular animal species. In one embodiment, asubject treated according to methods and using compositions of thepresent invention, can be mammalian or non-mammalian. In one embodiment,a mammalian subject can be any mammal including, but not limited to, ahuman; a non-human primate; a rodent such as a mouse, rat, or guineapig; a domesticated pet such as a cat or dog; a horse, cow, pig, sheep,goat, or rabbit. In one embodiment, a non-mammalian subject can be anynon-mammal including, but not limited to, a bird such as a duck, goose,chicken, or turkey. In one embodiment, subjects can be either gender andcan be any age. The composition and methods can also be used to preventcancer. The composition and methods can also be used to stimulate theimmune system.

The utility of the methods and compositions of the present invention isnot limited to any particular age of the subject. In one embodiment, asubject treated according to methods and using compositions of thepresent invention can be over the age of 50 years, over the age of 55years, over the age of 60 years, or over the age of 65 years. In oneembodiment a subject treated according to methods and using compositionsof the present invention can be under the age of 50 years, under the ageof 55 years, under the age of 60 years, or under the age of 65 years.

In one embodiment the subject has received at least one priortherapeutic agent. In one embodiment the subject has received at leasttwo, at least three, or at least four prior therapeutic agents. In oneembodiment the prior therapeutic agent is ibrutinib, bortezomib,carfilzomib, temozolomide, bevacizumab, cyclophosphamide,hydroxydaunorubicin, vincristine, prednisone, cytarabine, cisplatin,rituximab, 5-fluorouracil, oxaliplatin, leucovorin, or lenalidomide.

In one embodiment the subject has been treated with radiation. In oneembodiment the subject has been treated with surgery.

In some embodiments of the methods of treating a cancer, the cancer nolonger responds to treatment with ibrutinib, bortezomib, carfilzomib,temozolomide, bevacizumab, cyclophosphamide, hydroxydaunorubicin,vincristine, prednisone, cytarabine, cisplatin, rituximab,5-fluorouracil, oxaliplatin, leucovorin, lenalidomide, radiation,surgery, or a combination thereof.

In some embodiments, the compositions and methods of the presentinvention have dose response relation in cancer cells that is differentfrom dose response relation of the same the compositions and methods innormal cells. FIG. 1, for example, illustrates the dose responserelation in which effects of exemplary compound (1) on proliferation andcell death in normal and tumor cells. FIG. 1 shows cell viabilityfollowing treatment with exemplary compound (1) at indicatedconcentrations for 72 hours. The tumors tested included a human coloncancer cell line (HCT116), breast tumor cell line (MDA-MB-231), humanprimary glioblastoma cell line (U87). And the normal cells testedincluded human foreskin fibroblasts (HFF), human fetal lung fibroblast(MRC-5) cells, and human lung fibroblast cell line (WI-38). Doxorubicinwas used as a positive control at 1 μg/mL in normal fibroblasts. As,shown in FIG. 1, cell viability of normal cells tested is at least about75% at about 1-5 mg/mL concentration of exemplary compound (1) whereasviability of tumor cells is significantly lower (e.g., at or below 50%)at the same concentration of exemplary compound (1). Moreover, asconcentration of exemplary compound (1) is increased beyond about 5mg/mL viability of tumor cells falls to below 25% whereas viability ofnormal cells remains at about 75%.

FIG. 2 illustrates cell viability assay in human fetal lung fibroblast(MRC-5) cells following 72 hour treatment with exemplary compound (1) (5M) or DMSO and the indicated recovery period in complete drug-free mediaafter this treatment. The time points are given as time followingremoval of exemplary compound (1) after 72 hour treatment. As shown inFIG. 2, cell recovery was seen with exemplary compound (1), but not withDMSO.

In some embodiments, the compositions and methods of the presentinvention have utility in treating cancer in a subject. In oneembodiment, the compositions and methods of the present invention haveutility in treating cancer in a human subject. In one embodiment, themethod of treatment comprises administering to a subject in need of suchtreatment: (i) a first therapeutic agent including a compound comprisingcompound (1) or a pharmaceutically acceptable salt thereof incombination with (ii) a second therapeutic agent, wherein the firsttherapeutic agent and the second therapeutic agent are administeredeither simultaneously or sequentially. The second therapeutic agent canbe any suitable therapeutic agent, including any of the pharmaceuticallyactive agents disclosed in this application. In one embodiment, thepharmaceutically acceptable salt of compound (1) includes adi-hydrochloride salt having the structure of compound (2):

It is understood that compound (2), or an alternative di-salt thereofapparent from the teaching of this disclosure, can be substituted for acompound (1) in any of the compositions or dosing regimens describedherein.

In some embodiments, the method of treatment comprises administering toa subject in need of such treatment, a pharmaceutically effective amountof compound (1) or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

In some embodiments, the method of treatment of the present inventioncomprises administering a synergistic pharmaceutical combination, eithersimultaneously or sequentially, to a subject in need of such treatment,wherein the synergistic pharmaceutical combination comprising (i) afirst therapeutic agent comprising compound (1) or a pharmaceuticallyacceptable salt thereof; and (ii) a second therapeutic agent. In oneembodiment, the method of treatment comprises administering to a subjectin need of such treatment, either simultaneously or sequentially,therapeutically synergistic effective amounts of a first therapeuticagent comprising compound (1) or a pharmaceutically acceptable saltthereof in combination with a second therapeutic agent. In oneembodiment, the method of treatment comprises administering to a subjectin need of such treatment an effective amount of a first therapeuticagent comprising compound (1) or a pharmaceutically acceptable saltthereof in combination with an effective amount of a second therapeuticagent, wherein the combination provides a synergistic effect in the invivo treatment of cancer sensitive to the combination, and wherein thefirst therapeutic agent and the second therapeutic agent areadministered either simultaneously or sequentially. In one embodiment,the method of treatment comprises administering to a subject in need ofsuch treatment an effective amount of a first therapeutic agentcomprising compound (1) or a pharmaceutically acceptable salt thereof incombination with an effective amount of a second therapeutic agent,wherein the combination provides a synergistic effect in the in vivotreatment of a minimal residual disease sensitive to the combination,and wherein the first therapeutic agent and the second therapeutic agentare administered either simultaneously or sequentially.

In some embodiments, the second drug can be given before or prior tocompound (1).

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof solid tumors, liquid tumors, lymphomas, leukemias, or myelomas.

In one embodiment, the method of treatment of the present inventiontargets a solid tumor, wherein the solid tumor is selected from thegroup consisting of: Cervical Cancer, Endometrial Cancer, ExtracranialGerm Cell Tumor; Extragonadal Germ Cell Tumor; Germ Cell Tumor;Gestational Trophoblastic Tumor; Ovarian Cancer, Ovarian Germ CellTumor, Ovarian Epithelial Cancer, and Ovarian Low Malignant PotentialTumor; Penile Cancer, Prostate Cancer; Pregnancy and Breast Cancer; highgrade prostate cancer; medium grade prostate cancer; low grade prostatecancer; castration-resistant prostate cancer; Breast Cancer; Bile DuctCancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer;Hepatocellular (Liver) Cancer; Kidney (Renal Cell) Cancer; Liver Cancer,Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter; Basal CellCarcinoma; Basal Cell Nevus Syndrome, Gorlin-Nevus Syndrome, Melanoma,Merkel Cell Carcinoma, Papillomatosis, Multiple Endocrine NeoplasiaSyndrome; Pancreatic Cancer, Parathyroid Cancer, ocular melanoma; EyeCancer; Retinoblastoma; Malignant Fibrous Histiocytoma; Ewing SarcomaFamily of Tumors; desmoplastic round cell tumor; chondrosarcoma, KaposiSarcoma, Rhabdomyosarcoma; Spinal Cord Tumors, Leptomeningeal Disease,Central Nervous System Embryonal Tumors, Chordoma, Embryonal Tumors ofCentral Nervous System, Ependymoblastoma, Ependymoma, Neuroblastoma;Pineal Parenchymal Tumors of Intermediate Differentiation,Pineoblastoma; Adrenocortical Carcinoma; Bone Cancer, Osteosarcoma;Malignant Fibrous Histiocytoma of Bone and Osteosarcoma; Osteosarcomaand Malignant Fibrous Histiocytoma of Bone; Carcinoid Tumor, Carcinomaof Unknown Primary, Bronchial Tumors, Lung Cancer, PleuropulmonaryBlastoma; Respiratory Tract Carcinoma Involving the NUT Gene onChromosome 15, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor; CentralNervous System Atypical Teratoid/Rhabdoid Tumor, Craniopharyngioma,Glioma, Brain cancer, Medulloblastoma, Medulloepithelioma,Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor;Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor,Gastrointestinal Stromal Tumor (GIST), Bladder Cancer, Anal or RectalCancer, Appendix Cancer, Esophageal Cancer, Hypopharyngeal Cancer;Laryngeal Cancer, Lip and Oral Cavity Cancer, Metastatic Squamous NeckCancer with Occult Primary, Mouth Cancer, Nasal Cavity and ParanasalSinus Cancer, Nasopharyngeal Cancer, Oral Cancer, Lip and Oral CavityCancer, Oropharyngeal Cancer, Paranasal Sinus and Nasal Cavity Cancer,Pharyngeal Cancer; Head and Neck Cancer, and Mesothelioma.

In one embodiment, the method of treatment of the present inventiontargets lymphoma, wherein the lymphoma is selected from the groupconsisting of: diffuse large B-cell lymphoma, AIDS-Related Lymphoma,Cutaneous T-Cell Lymphoma, Sezary syndrome, mycosis fungoides (MF);Histiocytosis; Burkitt Lymphoma, and Central Nervous System Lymphoma;Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma,Hodgkin Lymphoma, Waldenstrom's macroglobulinemia; Mycosis Fungoides;Primary Central Nervous System Lymphoma; lymphoplasmacytic lymphoma, andPrimary Central Nervous System Lymphoma.

In one embodiment, the method of treatment of the present inventiontargets Non-Hodgkin's lymphoma (NHL), wherein the Non-Hodgkin's lymphomais selected from the group consisting of mantle cell lymphoma, diffuselarge B-cell lymphoma, follicular lymphoma, marginal zone lymphoma,small lymphocytic lymphoma, lyphoplasmacytic NHL, Waldenstrom'smacroglobulinaemia, and skin lymphomas.

In one embodiment, the method of treatment of the present inventiontargets leukemia, wherein the leukemia is selected from the groupconsisting of: Acute Lymphoblastic Leukemia (ALL), Chronic LymphocyticLeukemia (CLL), Chronic Myeloproliferative Disorders; Hairy CellLeukemia; Acute Myeloid Leukemia (AML); Chronic Myelogenous Leukemia(CML); and Langerhans Cell Histiocytosis.

In one embodiment, the method of treatment of the present inventiontargets acute leukemia, wherein the acute leukemia is selected from thegroup consisting of acute lymphotyte leukemia, acute myeloid leukemia,chronic lymphoblasitc leukemia, chronic myeloid leukemia,myelodysplastic syndrome, or myeloproliferative disease.

In one embodiment, the method of treatment of the present inventiontargets myeloma, wherein the myeloma is selected from the groupconsisting of: IgA myeloma; IgG myeloma; IgM myeloma; IgD myeloma; IgEmyeloma; light chain myeloma; non secretory myeloma; MultipleMyeloma/Plasma Cell Neoplasm, Multiple Myeloma, MyelodysplasticSyndromes, Myelodysplastic/Myeloproliferative Neoplasms,Myeloproliferative Disorders.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, AdrenocorticalCarcinoma, AIDS-Related Cancers, AIDS-Related Lymphoma, Anal or RectalCancer, Appendix Cancer, Astrocytomas, and Atypical Teratoid/RhabdoidTumor.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Basal Cell Carcinoma, Basal Cell Nevus Syndrome, Gorlin-NevusSyndrome, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Osteosarcomaand Malignant Fibrous Histiocytoma, Brain Tumor, Breast Cance, BronchialTumors, Burkitt Lymphoma, and Spinal Cord Tumors.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous SystemAtypical Teratoid/Rhabdoid Tumor, Central Nervous System EmbryonalTumors, Central Nervous System Lymphoma, Cervical Cancer, Chordoma,Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, ChronicMyeloproliferative Disorders, Colon Cancer, Colorectal Cancer,Craniopharyngioma, and Cutaneous T-Cell Lymphoma (including, but notlimited to Sezary syndrome and mycosis fungoides).

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Embryonal Tumors of Central Nervous System, Endometrial Cancer,Ependymoblastoma, Ependymoma, Esophageal Cancer, Ewing Sarcoma Family ofTumors, Desmoplastic Round Cell Tumor, Chondrosarcoma, Extracranial GermCell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer,and Eye Cancer, including Intraocular Melanoma and Retinoblastoma.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Gallbladder Cancer, Gastric (Stomach) Cancer, GastrointestinalCarcinoid Tumor, Gastrointestinal Stromal Tumor (GIST), Germ Cell Tumor,Gestational Trophoblastic Tumor, and Glioma.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver)Cancer, Histiocytosis, Hodgkin Lymphoma, and Hypopharyngeal Cancer.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Kaposi Sarcoma, and Kidney (Renal Cell) Cancer.

The method of treating cancer according to claim 1, wherein the canceris selected from the group consisting of Langerhans Cell Histiocytosis,Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer,including Non-Small Cell Lung Cancer, and Small Cell Lung Cance,Non-Hodgkin Lymphoma, and Primary Central Nervous System Lymphoma.

In one embodiment, the method of treatment of the present inventiontargets cancer, wherein the cancer is selected from the group consistingof Waldenstrim's macroglobulinemia (lymphoplasmacytic lymphoma),Malignant Fibrous Histiocytoma of Bone and Osteosarcoma,Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma,Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary,Multiple Endocrine Neoplasia Syndrome, Mouth Cancer, MultipleMyeloma/Plasma Cell Neoplasm, Mycosis Fungoides, MyelodysplasticSyndromes, Myelodysplastic/Myeloproliferative Neoplasms, MultipleMyeloma, and Myeloproliferative Disorders.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Nasal Cavity and Paranasal Sinus Cancer,Nasopharyngeal Cancer, and Neuroblastoma.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Oral Cancer, Lip and Oral Cavity Cancer,Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma ofBone, Ovarian Cancer, Ovarian Germ Cell Tumor, Ovarian EpithelialCancer, and Ovarian Low Malignant Potential Tumor.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Pancreatic Cancer, Papillomatosis, Paranasal Sinusand Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, PharyngealCancer, Pineal Parenchymal Tumors of Intermediate Differentiation,Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors,Pituitary Tumor, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer,Primary Central Nervous System Lymphoma, and Prostate Cancer.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Rectal Cancer, Renal Cell (Kidney) Cancer, RenalPelvis and Ureter, Respiratory Tract Carcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma, and Rhabdomyosarcoma.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Salivary Gland Cancer, Sarcoma, Sezary Syndrome,Skin Cancer, Skin Carcinoma, Small Intestine Cancer, Soft TissueSarcoma, Squamous Cell Carcinom, Squamous Neck Cancer with OccultPrimary, and Supratentorial Primitive Neuroectodermal Tumors.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of T-Cell Lymphoma, Testicular Cancer, Throat Cancer,Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancerof the Renal Pelvis and Ureter, and Gestational Trophoblastic Tumor.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Carcinoma of Unknown Primary Site, Cancer of UnknownPrimary Site, Unusual Cancers of Childhood, Transitional Cell Cancer Ofthe Renal Pelvis and Ureter, Urethral Cancer, and Uterine Sarcoma.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Vaginal Cancer, and Vulvar Cancer.

In one embodiment, the method of treatment of the present invention isuseful for treating cancer, wherein the cancer is selected from thegroup consisting of Wilms Tumor, and Women's Cancers.

In some embodiments, treatment of cancer comprises prevention of tumorgrowth in a cancer subject. In some embodiments, treatment of cancercomprises prevention of formation of cancer metastases in a cancersubject. In some embodiments, treatment of cancer comprises targetedtreatment of minimal residual disease in a cancer subject known to havethe minimal residual disease in a cancer or a subject at risk for havingminimal residual disease.

This might be indicated after treatment of the primary tumor by surgeryand/or after chemotherapy (e.g. radiotherapy) has been initiated ordetermined to efficacious. Disseminated tumor cells may be in theirdormant state and often cannot be attacked by the chemotherapy(radiotherapy). A thus treated patient seemingly is in a healed state,which is also described as “minimal residual disease”. Nevertheless, thedormant tumor cells have a potential of forming metastases if theybecome metastasizing cells due to a growth stimulus also after a longerdormant state.

As used herein, “minimal residual disease” denotes a small number ofcancer cells that remain in in a subject during treatment, or aftertreatment when the subject is in remission (exhibiting no symptoms orsigns of the disease). The methods described herein are preferablyapplied to any form of the diseases listed herein, including adult andchildhood forms of these diseases.

In one embodiment, the method of treatment of the present invention isuseful for treating an autoimmune disease. Autoimmune diseases include,but are not limited to alopecia areata, antiphospholipid, autoimmunehepatitis, celiac disease, diabetes type 1, Graves' disease,Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia,idiopathic thrombocytopenic purpura, inflammatory bowel disease,inflammatory myopathies, multiple sclerosis, primary biliary cirrhosis,psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome,systemic lupus erythematosus, and vitiligo.

In one embodiment, the method of treatment of the present invention isuseful for treating autoimmune and inflammatory disorders of theperipheral nerve system such as amyotrophic lateral sclerosis (LouGehrig's disease), based on various causes such as metabolic disordersthat include diabetes, B 12 and folate vitamin deficiencies,chemotherapy medications and medicines used to treat HIV, poisons thatcause peripheral nerve damage, cancers that develop peripheralneuropathies as well as paraneoplastic syndromes, alcohol abuse, chronickidney disease, injuries that cause compression on nerves and otherlesions, infections such as Lyme disease, Guillain Barre syndrome,connective tissue disease, rheumatoid arthritis, Sjogren's syndrome,systemic lupus erythematosus, certain inflammatory conditions such assarcoidosis, coeliac disease, hereditary diseases such as charcot marietooth syndrome, Friedreich's ataxia, and/or idiopathic where no specificcause is found but the inflammatory and/or autoimmune mechanisms are thecause of the onset.

In one embodiment, the method of treatment of the present invention isuseful for treating autoimmune and inflammatory disorders with ocularmanifestations. Such ocular manifestations include, but are not limitedto, ocular cicatricial pemphigoid, Mooren's corneal ulcer, various formsof uveitis, rheumatoid arthritis, systemic lupus erythematosus,polyarteritis nodosa, relapsing polychondritis, Wegener'sgranulomatosis, scleroderma, Behcet's disease, Reiter's disease,inflammatory bowel disease (ulcerative colitis and Crohn's disease) andankylosing spondylitis, retinitis pigmentosa, macular degeneration,keratoconjunctivitis sicca, scleritis, episcleritis, keratitis,peripheral corneal ulceration, and less common entities such aschoroiditis, retinal vasculitis, episcleral nodules, retinaldetachments, and/or macular edema.

In one embodiment, the method of treatment of the present invention isuseful for treating acute allograft rejection in transplant patients. Inone embodiment, the method of treatment of the present invention isuseful for treating ischemic stroke. In one embodiment, the method oftreatment of the present invention is useful for treating inflammatorydiseases. Inflammatory diseases include, but are not limited to,arthritis, psoriasis, asthma, and colitis.

In one embodiment, the first therapeutic agent includes apharmaceutically acceptable mono-salt of the compound (1). In oneembodiment, the first therapeutic agent includes a pharmaceuticallyacceptable di-salt of compound (1). As described herein, some of ouranalogues can be tri-salts In one embodiment, the first therapeuticagent includes compound (1) in the form of a pharmaceutically acceptablemono- or di-salt selected from the group consisting of hydrochloride,hydrobromide, hydrogensulphate, sulfates, phosphates, fumarates,succinates, oxalates and lactates, bisulfates, hydroxyl, tartrate,nitrate, citrate, bitartrate, carbonate, malate, maleate, fumaratesulfonate, methylsulfonate, formate, and carboxylate. In one embodiment,the first therapeutic agent includes compound (1) in the form of apharmaceutically acceptable mono- or di-salt selected fromp-toluene-sulfonate, benzenesulfonate, methanesulfonate, oxalate,succinate, tartrate, citrate, fumarate and maleate. In one embodiment,the first therapeutic agent includes compound (1) in the form of apharmaceutically acceptable mono- or di-salt having a counter ionselected from the group consisting of ammonium, sodium, potassium,calcium, magnesium, zinc, lithium, and/or with counter-ions such asmethylamino, dimethylamino, diethylamino, triethylamino counter-ions,and combinations thereof. In one embodiment, the first therapeutic agentincludes compound (1) n the form of a hydrochloride di-salt (i.e.,di-hydrochloride salt) or hydrobromide di-salt.

In some embodiments of the method of treatment, the second therapeuticagent includes an anti-cancer agent. In some embodiments of the methodof treatment, the second therapeutic agent is selected, withoutlimitation, from acivicin, aclarubicin, acodazole, acronine, adozelesin,aldesleukin, alitretinoin, allopurinol, altretamine, ambomycin,ametantrone, amifostine, aminoglutethimide, amsacrine, anastrozole,anthramycin, arsenic trioxide, asparaginase, asperlin, azacitidine,azetepa, azotomycin, batimastat, benzodepa, bevacizumab, bicalutamide,bisantrene, bisnafide dimesylate, bizelesin, bleomycin, brequinar,bropirimine, busulfan, cactinomycin, calusterone, capecitabine,caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin,cedefingol, celecoxib, chlorambucil, cirolemycin, cisplatin, cladribine,crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, decitabine, dexormaplatin, dezaguanine,dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, droloxifene,dromostanolone, duazomycin, edatrexate, eflomithine, elsamitrucin,enloplatin, enpromate, epipropidine, epirubicin, erbulozole, esorubicin,estramustine, etanidazole, etoposide, etoprine, fadrozole, fazarabine,fenretinide, floxuridine, fludarabine, fluorouracil, flurocitabine,fosquidone, fostriecin, fulvestrant, gemcitabine, hydroxyurea,idarubicin, ifosfamide, ilmofosine, interleukin II (IL-2, includingrecombinant interleukin II or rIL2), interferon alfa-2a, interferonalfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-Ia,interferon gamma-Ib, iproplatin, irinotecan, lanreotide, letrozole,leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol,maytansine, mechlorethamine hydrochlride, megestrol, melengestrolacetate, melphalan, menogaril, mercaptopurine, methotrexate, metoprine,meturedepa, mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin,mitomycin, mitosper, mitotane, mitoxantrone, mycophenolic acid,nelarabine, nocodazole, nogalamycin, ormnaplatin, oxisuran, paclitaxel,pegaspargase, peliomycin, pentamustine, peplomycin, perfosfamide,pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin,plomestane, porfimer, porfiromycin, prednimustine, procarbazine,puromycin, pyrazofurin, riboprine, rogletimide, safingol, semustine,simtrazene, sparfosate, sparsomycin, spirogermanium, spiromustine,spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin,tamoxifen, tecogalan, tegafur, teloxantrone, temoporfin, teniposide,teroxirone, testolactone, thiamiprine, thioguanine, thiotepa,tiazofurin, tirapazamine, topotecan, toremifene, trestolone,triciribine, trimetrexate, triptorelin, tubulozole, uracil mustard,uredepa, vapreotide, verteporfin, vinblastine, vincristine sulfate,vindesine, vinepidine, vinglycinate, vinleurosine, vinorelbine,vinrosidine, vinzolidine, vorozole, zeniplatin, zinostatin, zoledronate,zorubicin and combinations thereof.

In some embodiments of the method of treatment, the second therapeuticagent is selected, without limitation, from hormone analogues andantihormones, aromatase inhibitors, LHRH agonists and antagonists,inhibitors of growth factors, growth factor antibodies, growth factorreceptor antibodies, tyrosine kinase inhibitors; antimetabolites;antitumour antibiotics; platinum derivatives; alkylation agents;antimitotic agents; tubuline inhibitors; PARP inhibitors, topoisomeraseinhibitors, serine/threonine kinase inhibitors, tyrosine kinaseinhibitors, protein protein interaction inhibitors, MEK inhibitors, ERKinhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycinanalogs, amifostin, anagrelid, clodronat, filgrastin, interferon,interferon alpha, leucovorin, rituximab, procarbazine, levamisole,mesna, mitotane, pamidronate and porfimer, 2-chlorodesoxyadenosine,2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethine,131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B,A 105972, A 204197, abiraterone, aldesleukin, alitretinoin,allovectin-7, altretamine, alvocidib, amonafide, anthrapyrazole,AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene,atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, AMG-479(ganitumab), ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244(selumetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717,AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib),avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006,BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, BEZ-235, biricodardicitrate, BCX-1777, BKM-120, bleocin, BLP-25, BMS-184476, BMS-247550,BMS-188797, BMS-275291, BMS-663513, BMS-754807, BNP-1350, BNP-7787, BIBW2992 (afatinib, tomtovok), BIBF 1120 (vargatef), BI 836845, BI 2536, BI6727, BI 836845, BI 847325, BI 853520, BUB-022, bleomycinic acid,bleomycin A, bleomycin B, brivanib, bryostatin-1, bortezomib,brostallicin, busulphan, BYL-719, CA-4 prodrug, CA-4, CapCell,calcitriol, canertinib, canfosfamide, capecitabine,carboxyphthalatoplatin, CC1-779, CC-115, CC-223, CEP-701, CEP-751, CBT-1cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin,CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin,CDA-II, CDC-394, CKD-602, CKI-27, clofarabin, colchicin, combretastatinA4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 cryptophycin52, CTP-37, CTLA-4 monoclonal antibodies, CP-461, CV-247,cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine,deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010,E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFRinhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin,epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3,ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate,exemestane, exisulind, fenretinide, figitumumab, floxuridine, folicacid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fotemustine, galarubicin,gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide,GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068,GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptidevaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436(dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183,GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine,histamine, homoharringtonine, hyaluronic acid, hydroxyurea,hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate,idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12(cixutumumab), immunol, indisulam, interferon alpha-2a, interferonalpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117,INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide,leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin,lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301,mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf ingadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar,neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin,N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage,oncoVEXGM-CSF, ormiplatin, ortataxel, OX44 antibodies, OSI-027, OSI-906(linsitinib), 4-1BB antibodies, oxantrazole, oestrogen, panitumumab,patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204,PD0325901, PD-1 antibodies, PEG-paclitaxel, albumin-stabilizedpaclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427,P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine,perillylalcohol, pertuzumab, PI3K inhibitors, PI3K/mTOR inhibitors,PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054,PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate,pixantrone, phenoxodiol 0, PKI166, plevitrexed, plicamycin, polyprenicacid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin,R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436,rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors,revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb,rinfabate, risedronate, rituximab, robatumumab, rofecoxib, RO-31-7453,RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan,R-flurbiprofen, RX-0201, S-9788, sabarubicin, SAHA, sargramostim,satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101,semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747,SR-13668, SRL-172, sorafenib, spiroplatin, squalamine,suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103,tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere,taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene,testosterone, testosterone propionate, tesmilifene, tetraplatin,tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin,thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine,tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinicacid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine,triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin,valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1,WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281,XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474,ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronat,zosuquidar, and combinations thereof.

In some embodiments of the method of treatment, the second therapeuticagent is selected from the group consisting of tamoxifen, toremifene,raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide,bicalutamide, aminoglutethimide, cyproterone acetate, finasteride,buserelin acetate, fludrocortisone, fluoxymesterone,medroxy-progesterone, octreotide, and combinations thereof. In someembodiments of the method of treatment, the second therapeutic agent isselected, without limitation, from the group consisting of LHRH agonistsand LHRH antagonists. In some embodiments of the method of treatment,the second therapeutic agent includes a LHRH agonist selected from thegroup consisting of goserelin acetate, luprolide acetate, triptorelinpamoate and combinations thereof. In some embodiments of the method oftreatment, the second therapeutic agent includes a LHRH antagonistselected from the group consisting of wherein the LHRH antagonists areselected from the group consisting of Degarelix, Cetrorelix, Abarelix,Ozarelix, Degarelix combinations thereof. In some embodiments of themethod of treatment, the second therapeutic agent includes an inhibitorof a growth factor. In some embodiments of the method of treatment, ofthe second therapeutic agent, the inhibitor of the growth factor isselected, without limitation, from the group consisting of inhibitorsof: platelet derived growth factor (PDGF), fibroblast growth factor(FGF), vascular endothelial growth factor (VEGF), epidermal growthfactor (EGF), insuline-like growth factors (IGF), human epidermal growthfactor (HER), hepatocyte growth factor (HGF), and combinations thereof.In some embodiments of the method of treatment, the second therapeuticagent includes

In some embodiments of the method of treatment, the second therapeuticagent includes an inhibitor of a growth factor. In some embodiments ofthe method of treatment, the second therapeutic agent includes aninhibitor of the human epidermal growth factor (HER). In someembodiments of the method of treatment, the second therapeutic agentincludes an inhibitor of a growth factor selected from the groupconsisting of: platelet derived growth factor (PDGF), fibroblast growthfactor (FGF), vascular endothelial growth factor (VEGF), epidermalgrowth factor (EGF), insuline-like growth factors (IGF), human epidermalgrowth factor (HER) and hepatocyte growth factor (HGF). In someembodiments of the method of treatment, the second therapeutic agentincludes n inhibitor of the human epidermal growth factor (HER). In someembodiments of the method of treatment, the second therapeutic agentincludes an inhibitor of the human epidermal growth factor (HER)selected from the group consisting of HER2, HER3, and HER4. In someembodiments of the method of treatment, the second therapeutic agentincludes a tyrosine kinase inhibitor. In some embodiments of the methodof treatment, the second therapeutic agent includes a tyrosine kinaseinhibitor selected, without limitation, from the group consisting ofcetuximab, gefitinib, imatinib, lapatinib and trastuzumab, andcombinations thereof. In some embodiments of the method of treatment,the second therapeutic agent includes an aromatase inhibitor. In someembodiments of the method of treatment, the second therapeutic agentincludes an aromatase inhibitor selected from the group consisting ofanastrozole, letrozole, liarozole, vorozole, exemestane, atamestane, andcombinations thereof.

In some embodiments of the method of treatment, the second therapeuticagent includes an antimetabolite. In some embodiments of the method oftreatment, the second therapeutic agent includes an antimetabolite thatcomprises an antifolate. In some embodiments of the method of treatment,the second therapeutic agent includes an antifolate selected from thegroup consisting of methotrexate, raltitrexed, pyrimidine analogues, andcombinations thereof. In some embodiments of the method of treatment,the second therapeutic agent includes an antimetabolite that ispyrimidine analogue. In some embodiments of the method of treatment, thesecond therapeutic agent includes a pyrimidine analogue selected fromthe group consisting of 5-fluorouracil, capecitabin, gemcitabin, andcombination thereof. In some embodiments of the method of treatment, thesecond therapeutic agent includes an antimetabolite that is a purineanalogue or adenosine analogue. In some embodiments of the method oftreatment, the second therapeutic agent includes a a purine analogue oradenosine analogue selected from the group consisting of mercaptopurine,thioguanine, cladribine and pentostatin, cytarabine, fludarabine, andcombinations thereof. In some embodiments of the method of treatment,the second therapeutic agent includes an antitumour antibiotic. In someembodiments of the method of treatment, the antitumor antibiotic isselected from the group consisting of anthracyclins, doxorubicin,daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin,dactinomycin, plicamycin, streptozocin and combinations thereof. In someembodiments of the method of treatment, the second therapeutic agentincludes a platinum derivative. In some embodiments of the method oftreatment, the platinum derivative is selected from the group consistingof cisplatin, oxaliplatin, carboplatin and combinations thereof. In someembodiments of the method of treatment, the second therapeutic agentincludes an alkylation agent. In some embodiments of the method oftreatment, the second therapeutic agent includes an alkylation agentselected from the group consisting of estramustin, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide,ifosfamide, temozolomide, nitrosoureas, and combinations thereof. Insome embodiments of the method of treatment, the second therapeuticagent includes a nitrosourea. In some embodiments of the method oftreatment, the second therapeutic agent includes a nitrosourea selectedfrom the group consisting of carmustin, lomustin, thiotepa, andcombinations thereof. In some embodiments of the method of treatment,the second therapeutic agent includes an antimitotic agent. In someembodiments of the method of treatment, the second therapeutic agentincludes an antimitotic agent selected from the group consisting ofVinca alkaloids and taxanes. In some embodiments of the method oftreatment, the second therapeutic agent includes a taxane selected fromthe group consisting of paclitaxel, docetaxel, and combinations thereof.In some embodiments of the method of treatment, the second therapeuticagent includes a Vinca alkaloids are selected from the group consistingof vinblastine, vindesin, vinorelbin, vincristine, and combinationsthereof. In some embodiments of the method of treatment, the secondtherapeutic agent includes a topoisomerase inhibitor. In someembodiments of the method of treatment, the second therapeutic agentincludes a topoisomerase inhibitor which is an epipodophyllotoxin. Insome embodiments of the method of treatment, the second therapeuticagent includes a topoisomerase inhibitor, which is a epipodophyllotoxinsselected from the group consisting of etoposide and etopophos,teniposide, amsacrin, topotecan, irinotecan, mitoxantron, andcombinations thereof. In some embodiments of the method of treatment,the second therapeutic agent includes a serine/threonine kinaseinhibitor. In some embodiments of the method of treatment, the secondtherapeutic agent includes a serine/threonine kinase inhibitor selectedfrom the group consisting of PDK 1 inhibitors, B-Raf inhibitors, mTORinhibitors, mTORC1 inhibitors, PI3K inhibitors, dual mTOR/PI3Kinhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors,inhibitors of CDKs, Aurora kinase inhibitors, and combinations thereof.In some embodiments of the method of treatment, the second therapeuticagent includes a tyrosine kinase inhibitor. In some embodiments of themethod of treatment, the second therapeutic agent includes a PTK2/FAKinhibitor. In some embodiments of the method of treatment, the secondtherapeutic agent includes a protein protein interaction inhibitor. Insome embodiments of the method of treatment, the second therapeuticagent includes a protein protein interaction inhibitor selected from thegroup consisting of IAP, Mcl-1, MDM2/MDMX and combinations thereof. Insome embodiments of the method of treatment, the second therapeuticagent includes a rapamycin analog. In some embodiments of the method oftreatment, the second therapeutic agent includes a rapamycin analogselected from the group consisting of everolimus, temsirolimus,ridaforolimus, sirolimus, and combinations thereof. In some embodimentsof the method of treatment, the second therapeutic agent is selectedfrom the group consisting of amifostin, anagrelid, clodronat,filgrastin, interferon, interferon alpha, leucovorin, rituximab,procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer, andcombinations thereof. In some embodiments of the method of treatment,the second therapeutic agent is selected from the group consisting of2-chlorodesoxyadenosine, 2-fluorodesoxy-cytidine, 2-methoxyoestradiol,2C4,3-alethine, 131-1-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin,16-aza-epothilone B, A 105972, A 204197, abiraterone, aldesleukin,alitretinoin, allovectin-7, altretamine, alvocidib, amonafide,anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose,arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB,AZ10992, ABX-EGF, AMG-479 (ganitumab), ARRY 162, ARRY 438162, ARRY-300,ARRY-142886/AZD-6244 (selumetinib), ARRY-704/AZD-8330, AR-12, AR-42,AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680,AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothiloneB, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab,BEZ-235, biricodar dicitrate, BCX-1777, BKM-120, bleocin, BLP-25,BMS-184476, BMS-247550, BMS-188797, BMS-275291, BMS-663513, BMS-754807,BNP-1350, BNP-7787, BIBW 2992 (afatinib, tomtovok), BIBF 1120(vargatef), BI 836845, BI 2536, BI 6727, BI 836845, BI 847325, BI853520, BUB-022, bleomycinic acid, bleomycin A, bleomycin B, brivanib,bryostatin-1, bortezomib, brostallicin, busulphan, BYL-719, CA-4prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide,capecitabine, carboxyphthalatoplatin, CC1-779, CC-115, CC-223, CEP-701,CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib,celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene,cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, CKI-27, clofarabin,colchicin, combretastatin A4, COT inhibitors, CHS-828, CH-5132799,CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CTLA-4 monoclonal antibodies,CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851,decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide,desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol,diflomotecan, didox, DMDC, dolastatin 10, doranidazole, DS-7423, E7010,E-6201, edatrexat, edotreotide, efaproxiral, eflornithine, EGFRinhibitors, EKB-569, EKB-509, enzastaurin, enzalutamide, elsamitrucin,epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-0CH3,ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate,exemestane, exisulind, fenretinide, figitumumab, floxuridine, folicacid, FOLFOX, FOLFOX4, FOLFIRI, formestane, fotemustine, galarubicin,gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide,GCS-100, GDC-0623, GDC-0941 (pictrelisib), GDC-0980, GDC-0032, GDC-0068,GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gp100-peptidevaccines, GSK-5126766, GSK-690693, GSK-1120212 (trametinib), GSK-2118436(dabrafenib), GSK-2126458, GSK-2132231A, GSK-2334470, GSK-2110183,GSK-2141795, GW2016, granisetron, herceptine, hexamethylmelamine,histamine, homoharringtonine, hyaluronic acid, hydroxyurea,hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate,idenestrol, IDN-5109, IGF-1R inhibitors, IMC-1C11, IMC-A12(cixutumumab), immunol, indisulam, interferon alpha-2a, interferonalpha-2b, pegylated interferon alpha-2b, interleukin-2, INK-1117,INK-128, INSM-18, ionafarnib, ipilimumab, iproplatin, irofulven,isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2,JSF-154, J-107088, conjugated oestrogens, kahalid F, ketoconazole,KW-2170, KW-2450, lobaplatin, leflunomide, lenograstim, leuprolide,leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin,lometrexol, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, LY-2780301,mafosfamide, marimastat, mechloroethamine, MEK inhibitors, MEK-162,methyltestosteron, methylprednisolone, MEDI-573, MEN-10755, MDX-H210,MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin,mivobulin, MK-2206, MK-0646 (dalotuzumab), MLN518, motexaf ingadolinium, MS-209, MS-275, MX6, neridronate, neratinib, Nexavar,neovastat, nilotinib, nimesulide, nitroglycerin, nolatrexed, norelin,N-acetylcysteine, 06-benzylguanine, oblimersen, omeprazole, oncophage,oncoVEXGM-CSF, ormiplatin, ortataxel, OX44 antibodies, OSI-027, OSI-906(linsitinib), 4-1BB antibodies, oxantrazole, oestrogen, panitumumab,patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PBI-05204,PD0325901, PD-1 antibodies, PEG-paclitaxel, albumin-stabilizedpaclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427,P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine,perillylalcohol, pertuzumab, PI3K inhibitors, PI3K/mTOR inhibitors,PG-TXL, PG2, PLX-4032/RO-5185426 (vemurafenib), PLX-3603/RO-5212054,PT-100, PWT-33597, PX-866, picoplatin, pivaloyloxymethylbutyrate,pixantrone, phenoxodiol 0, PKI166, plevitrexed, plicamycin, polyprenicacid, porfiromycin, prednisone, prednisolone, quinamed, quinupristin,R115777, RAF-265, ramosetron, ranpirnase, RDEA-119/BAY 869766, RDEA-436,rebeccamycin analogues, receptor tyrosine kinase (RTK) inhibitors,revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizoxin, rhu-MAb,rinfabate, risedronate, rituximab, robatumumab, rofecoxib, RO-31-7453,RO-5126766, RO-5068760, RPR 109881A, rubidazone, rubitecan,R-flurbiprofen, RX-0201, S-9788, sabarubicin, SAHA, sargramostim,satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101,semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747,SR-13668, SRL-172, sorafenib, spiroplatin, squalamine,suberanilohydroxamic acid, sutent, T 900607, T 138067, TAK-733, TAS-103,tacedinaline, talaporf in, Tarceva, tariquitar, tasisulam, taxotere,taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene,testosterone, testosterone propionate, tesmilifene, tetraplatin,tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin,thymalfasin, thymectacin, tiazofurin, tipifarnib, tirapazamine,tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinicacid, traszutumab, tremelimumab, tretinoin, triacetyluridine, triapine,triciribine, trimetrexate, TLK-286TXD 258, tykerb/tyverb, urocidin,valrubicin, vatalanib, vincristine, vinflunine, virulizin, WX-UK1,WX-554, vectibix, xeloda, XELOX, XL-147, XL-228, XL-281,XL-518/R-7420/GDC-0973, XL-765, YM-511, YM-598, ZD-4190, ZD-6474,ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronat,zosuquidar, and combinations thereof.

In some embodiments, the at least one other therapeutic agent comprisesa steroid. Steroids include, but are not limited to, dexamethasone,prednisolone, methyl prednisolone, prednisone, hydrocortisone,triamcinolone, betamethasone, and cortivazol. In some embodiments, theat least one other therapeutic agent comprises an anti-emetic.Anti-emetics include, but are not limited to, 5-HT3 receptor agonists(such as dolasetron, granisetron, ondansetron, tropisetron,palonosetron, and mirtazapine), dopamine agonists (such as domperidone,olanzapine, droperidol, haloperidol, chlorpromazine, prochlorperazine,alizapride, prochlorperazine, and metoclopramide), NK1 receptorantagonists (such as aprepitant and casopitant), antihistamines (such ascyclizine, diphenhydramine, dimenhydrinate, doxylamine, meclizine,promethazine, hydroxyzine), cannabinoids (such as cannabis, dronabinol,nabilone, and sativex), benzodiazepines (such as midazolam andlorazepam), anticholinergics (such as hyoscine), trimethobenzamide,ginger, emetrol, propofol, peppermint, muscimol, and ajwain.

The pharmaceutical compositions of the present invention may beadministered to a subject via any suitable route of administration. Inone embodiment, the pharmaceutical composition is administered to asubject orally, parenterally, transdermally or transmucosally. In oneembodiment, the pharmaceutical composition is administered to a subjectin a parenteral dosage form. In one embodiment, the pharmaceuticalcomposition is administered to a subject as a parenterally. In oneembodiment, the pharmaceutical composition is administered to a subjectvia a parenteral route of administration selected from the groupconsisting of intravenous (IV), subcutaneous (SC), and intramuscular(IM). In one embodiment, the pharmaceutical composition is administeredto a subject via a route of administration selected from rectal (PR) andtransdermal. In one embodiment, the pharmaceutical composition isadministered to a subject in a dosage form selected from the groupconsisting of sterile solutions, suspensions, suppositories, tablets andcapsules. In one embodiment, the pharmaceutical composition isadministered to a subject in an oral dosage form selected from the groupconsisting of a tablet, caplet, capsule, lozenge, syrup, liquid,suspension and elixir. In one embodiment, the pharmaceutical compositionis administered to a subject in an oral dosage form selected from thegroup consisting of tablets, hard shell capsules, soft gelatin capsules,beads, granules, aggregates, powders, gels, solids and semi-solids.

In some embodiments, the pharmaceutical composition is in administeredto a subject as a dosage form selected from the group consisting ofsustained release forms, controlled release forms, delayed release formsand response release forms.

In some embodiments, the pharmaceutical composition in accordance withthe present invention is administered to a subject once daily. In someembodiments, a pharmaceutical composition in accordance with the presentinvention is administered to a subject according to an infrequent dosingregimen (e.g., administered once per week or less frequently). In someembodiments, a pharmaceutical composition in accordance with the presentinvention is administered to a subject according to a frequent dosingregimen (e.g., administered more than once per week). In someembodiments, the pharmaceutical composition in accordance with thepresent invention is administered to a subject once weekly. In someembodiments, the pharmaceutical composition in accordance with thepresent invention is administered to a subject once every four weeks. Insome embodiments, the pharmaceutical composition in accordance with thepresent invention is administered to a subject twice a week. In someembodiments, the pharmaceutical composition in accordance with thepresent invention is administered to a subject once every two weeks. Insome embodiments, the pharmaceutical composition in accordance with thepresent invention is administered to a subject once every three weeks.In some embodiments, the pharmaceutical composition in accordance withthe present invention is administered to a subject in a repeated cycleof once weekly, once every two weeks, once every three weeks, once everyfour weeks or combinations thereof.

In one embodiment, the method of treatment comprises administering to asubject in need of such treatment: (i) a first therapeutic agentincluding a compound comprising compound (1) or a pharmaceuticallyacceptable salt thereof in combination with (ii) a second therapeuticagent, wherein the first therapeutic agent and the second therapeuticagent are administered either simultaneously or sequentially; andfurther comprises assaying the expression of an endoplasmic reticulum(ER) stress response genes in a biological sample. In some embodimentsthe endoplasmic reticulum stress response gene is selected from thegroup that includes, but is not limited to, C/EBP-Homologous Protein(CHOP), Activating Transcription Factor 3 (ATF3) and both CHOP and ATF3.The biological sample may be tumor, peripheral blood mononuclear cells,or skin biopsy. The biological sample may be obtained before, during, orafter drug administration. In some embodiments, the method of treatmentfurther comprises adjusting a dose of compound (1) to achieve inductionof about 50%, 75%, 100%, 125%, 150%, 175%, 200%, 225%, 250%, 275%, 300%,325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, 525%, 550%, 575%, 600%,or greater than 600% of one or more ER stress gene(s). In someembodiments, the method of treatment further comprises adjusting a doseof compound (1) to achieve induction of about 50% to about 100%, about100% to about 150%, about 150% to about 200%, about 200% to about 250%,about 250% to about 300%, about 300% to about 350%, about 350% to about400%, about 400% to about 450%, about 450% to about 500%, about 500% toabout 550%, about 550% to about 600%, or greater than 600% of the ERstress gene. In some embodiments, the method of treatment furthercomprises adjusting a dose of compound (1) to achieve induction of about50% to about 100%, about 100% to about 200%, about 200% to about 300%,about 300% to about 400%, about 400% to about 500%, about 500% to about600%, or greater than 600% of the ER stress gene.

In one embodiment, the method of treatment comprises administering to asubject in need of such treatment: (i) a first therapeutic agentincluding a compound comprising compound (1) or a pharmaceuticallyacceptable salt thereof in combination with (ii) a second therapeuticagent, wherein the first therapeutic agent and the second therapeuticagent are administered either simultaneously or sequentially; andfurther comprises assaying the expression of a proteasomal activity in abiological sample. In some embodiments the proteasomal activity may bechymotrysin-like, trypsin-like, and/or caspase-like activity. In someembodiments the biological sample may be tumor, peripheral bloodmononuclear cells, or skin cells. The biological sample may be obtainedbefore, during, or after drug administration. In some embodiments, themethod of treatment further comprises adjusting the dose to achieveinhibition of about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, or about 100% of theproteasomal activity. In some embodiments, the method of treatmentfurther comprises adjusting the dose to achieve inhibition of at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least95% of the proteasomal activity. In some embodiments, the method oftreatment further comprises adjusting the dose to achieve inhibition ofabout 20% to about 30%, about 30% to about 40%, about 40% to about 50%,about 50% to about 60%, about 60% to about 70%, about 70% to about 80%,about 80% to about 90%, or greater than 90% of the proteasomal activity.

In an aspect, the present invention provides a method of treatment,which comprises administering to a subject in need of such treatment acombination of a first therapeutic agent including the followingcompound (1) and a second therapeutic agent, the method comprising: (i)administering to the subject the first therapeutic agent includingcompound (1):

or a pharmaceutically acceptable salt (e.g., a di-salt or tri-salt)thereof;

(ii) waiting until a predetermined waiting time has elapsed after thetime of administration of the first therapeutic agent to the subject;and/or until adverse events are resolved or resolving; and

(iii) administering the second therapeutic agent to the subject, whereinthe predetermined waiting time is chosen so as to obtain a delayedtherapeutic effect of the first therapeutic agent without an increasedrisk of possible combined toxic effects of the first and secondtherapeutic agents. In some embodiments of the method of treatment, thepredetermined waiting time is determined based on the clearance rate ofcompound (1) or the pharmaceutically acceptable salt thereof. In someembodiments of the method of treatment, the predetermined waiting timeis determined by a quantitative assessment of renal function andparameters of renal. In some embodiments of the method of treatment, thepredetermined waiting time is determined by an assays for thedetermination of renal function, wherein the assay is selected from thegroup consisting of serum level of compound (1) or the pharmaceuticallyacceptable salt thereof; compound (1) or the pharmaceutically acceptablesalt thereof clearance rate; 24-hour urinary clearance of compound (1)or the pharmaceutically acceptable salt thereof or a metabolite thereof.

In one embodiment of the method of treatment, the predetermined waitingtime substantially equals to the time required for systemic clearance ofcompound (1) or a pharmaceutically acceptable salt thereof from the bodyof the subject. In one embodiment of the method of treatment, thepredetermined waiting time substantially equals to the time required forrenal clearance of compound (1) or a pharmaceutically acceptable saltthereof from the body of the subject. In one embodiment of the method oftreatment, the predetermined waiting time substantially equals to thetime required for hepatic clearance of compound (1) or apharmaceutically acceptable salt thereof from the body of the subject.In one embodiment of the method of treatment, the predetermined waitingtime substantially equals to the time required for total clearance ofcompound (1) or a pharmaceutically acceptable salt thereof from the bodyof the subject. In one embodiment of the method of treatment, thepredetermined waiting time is about 4 hours. In other embodiments thewaiting time is 1 day. In some embodiments, the wait time is until Cmaxof compound (1) has passed. In other embodiments, the waiting time isafter most of the adverse events are resolved or are resolving. In oneembodiment of the method of treatment, the predetermined waiting time isabout 2 days. In one embodiment of the method of treatment, thepredetermined waiting time is about 3 days. In one embodiment of themethod of treatment, the predetermined waiting time is about 4 days. Inone embodiment of the method of treatment, the predetermined waitingtime is about 5 days. In one embodiment of the method of treatment, thepredetermined waiting time is about 6 days. In one embodiment of themethod of treatment, the predetermined waiting time is about 7 days. Inone embodiment of the method of treatment, the predetermined waitingtime is about 1-7 days. In one embodiment of the method of treatment,the predetermined waiting time is about 1-6 days. In one embodiment ofthe method of treatment, the predetermined waiting time is about 1-5days. In one embodiment of the method of treatment, the predeterminedwaiting time is about 1-4 days. In one embodiment of the method oftreatment, the predetermined waiting time is about 1-3 days. In oneembodiment of the method of treatment, the predetermined waiting time isabout 1 to 2 days. In some embodiments, the waiting time is up to 3weeks. The preceeding are considered “therapeutic time periods.”

When the order of administration is reversed, timing for theadministration of compound (1) can be after the Cmax of the firstadministered drug has passed. In some embodiments, administration ofcompound (1) can be after most or substantially all of the firstadministered drug has been eliminated from the body or the toxicityeffects for the first administered drug are resolved or are resolving.

In some embodiments, the method of treatment further comprisesmonitoring level of compound (1), a pharmaceutically acceptable saltthereof, or a metabolite thereof in the subject using pharmacokineticprofiling. In some such embodiments, monitoring level of compound (1), apharmaceutically acceptable salt thereof, or a metabolite thereof in thesubject using pharmacokinetic profiling comprises constructing apharmacokinetic profile of compound (1), a pharmaceutically acceptablesalt thereof, or a metabolite thereof for the subject usingconcentrations of compound (1), a pharmaceutically acceptable saltthereof, or a metabolite thereof in at least two samples obtained fromthe subject at time points suitable to construct a pharmacokineticprofile. In some embodiments of the method, which include monitoringlevel of compound (1), a pharmaceutically acceptable salt thereof, or ametabolite thereof in the subject using pharmacokinetic profiling, atleast two samples are collected from the subject at point-of-care orpoint of use by sampling or self-sampling on point-of-care devices orpoint of use devices or on matrices suitable for storage of the at leasttwo samples prior to quantitation in a laboratory. In some embodimentsof the method of treatment, each of the point-of-care devices or pointof use devices is capable of quantitating compound (1), apharmaceutically acceptable salt thereof, or a metabolite. In someembodiments of the method, which include monitoring level of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofin the subject, one or more samples are collected from the subject atpoint-of-care or point of use by biopsy device for analysis at thepoint-of-care or point of use devices or for storage prior to analysisby a laboratory. In some embodiments of the method, a biopsy is takenafter a time interval of 3-8 hours following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject. In some embodiments of the method, a biopsy is takenafter a time interval of 3-24 hours following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject. In some embodiments of the method, a biopsy is takenafter a time interval of 8-24 hours following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject. In some embodiments of the method, a biopsy is takenafter a time interval of 2 days following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject. In some embodiments of the method, a biopsy is takenafter a time interval of 3 days following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject. In some embodiments of the method, a biopsy is takenafter a time interval of 4 days following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject. In some embodiments of the method, a biopsy is takenafter a time interval of 1-7 days following administration of compound(1), a pharmaceutically acceptable salt thereof, or a metabolite thereofto the subject.

In some embodiments of the method of treatment, the pharmacokineticprofile includes pharmacokinetic parameters suitable for guiding dosingof compound (1) or a pharmaceutically acceptable salt thereof for thesubject being treated. In some embodiments of the method of treatment,maximum concentration of the first therapeutic agent in blood (wholeblood, plasma, or serum) (“Cmax”) of the subject following itsadministration to the subject ranges from about 1000 ng/dl to 1500 ng/dlfor a therapeutic time period. In some embodiments, Cmax is less than1500 ng/dl and greater than 85 ng/dl for a therapeutic time period. Insome embodiments of the method of treatment, maximum concentration ofthe first therapeutic agent in blood (whole blood, plasma, or serum)(“Cmax”) of the subject following its administration to the subjectranges from about 1000 ng/ml to 1500 ng/ml for a therapeutic timeperiod. In some embodiments, Cmax is less than 1500 ng/ml and greaterthan 85 ng/ml for a therapeutic time period.

In some embodiments, maximum concentration of the first therapeuticagent in blood (whole blood, plasma, or serum) (“Cmax”) of the subjectfollowing its administration to the subject is a Cmax of from about 1000ng/dl to about 1500 ng/dl, from about 1010 ng/dl to about 1500 ng/dl,from about 1020 ng/dl to about 1500 ng/dl, from about 1030 ng/dl toabout 1500 ng/dl, from about 1040 ng/dl to about 1500 ng/dl, from about1050 ng/dl to about 1500 ng/dl, from about 1060 ng/dl to about 1500ng/dl, from about 1070 ng/dl to about 1500 ng/dl, from about 1080 ng/dlto about 1500 ng/dl, from about 1090 ng/dl to about 1500 ng/dl, fromabout 1100 ng/dl to about 1500 ng/dl, from about 1110 ng/dl to about1500 ng/dl, from about 1120 ng/dl to about 1500 ng/dl, from about 1130ng/dl to about 1500 ng/dl, from about 1140 ng/dl to about 1500 ng/dl,from about 1150 ng/dl to about 1500 ng/dl, from about 1160 ng/dl toabout 1500 ng/dl, from about 1170 ng/dl to about 1500 ng/dl, from about1180 ng/dl to about 1500 ng/dl, from about 1190 ng/dl to about 1500ng/dl, from about 1200 ng/dl to about 1500 ng/dl, from about 1210 ng/dlto about 1500 ng/dl, from about 1220 ng/dl to about 1500 ng/dl, fromabout 1230 ng/dl to about 1500 ng/dl, from about 1240 ng/dl to about1500 ng/dl, from about 1250 ng/dl to about 1500 ng/dl, from about 1260ng/dl to about 1500 ng/dl, from about 1270 ng/dl to about 1500 ng/dl,from about 1280 ng/dl to about 1500 ng/dl, from about 1290 ng/dl toabout 1500 ng/dl, from about 1300 ng/dl to about 1500 ng/dl, from about1310 ng/dl to about 1500 ng/dl, from about 1320 ng/dl to about 1500ng/dl, from about 1330 ng/dl to about 1500 ng/dl, from about 1340 ng/dlto about 1500 ng/dl, from about 1350 ng/dl to about 1500 ng/dl, fromabout 1360 ng/dl to about 1500 ng/dl, from about 1370 ng/dl to about1500 ng/dl, from about 1380 ng/dl to about 1500 ng/dl, from about 1390ng/dl to about 1500 ng/dl, from about 1400 ng/dl to about 1500 ng/dl,from about 1410 ng/dl to about 1500 ng/dl, from about 1420 ng/dl toabout 1500 ng/dl, from about 1430 ng/dl to about 1500 ng/dl, from about1440 ng/dl to about 1500 ng/dl, from about 1450 ng/dl to about 1500ng/dl, from about 1460 ng/dl to about 1500 ng/dl, from about 1470 ng/dlto about 1500 ng/dl, from about 1480 ng/dl to about 1500 ng/dl, or fromabout 1490 ng/dl to about 1500 ng/dl.

In some embodiments, maximum concentration of the first therapeuticagent in blood (whole blood, plasma, or serum) (“Cmax”) of the subjectfollowing its administration to the subject is a Cmax of from about 1000ng/ml to about 1500 ng/ml, from about 1010 ng/ml to about 1500 ng/ml,from about 1020 ng/ml to about 1500 ng/ml, from about 1030 ng/ml toabout 1500 ng/ml, from about 1040 ng/ml to about 1500 ng/ml, from about1050 ng/ml to about 1500 ng/ml, from about 1060 ng/ml to about 1500ng/ml, from about 1070 ng/ml to about 1500 ng/ml, from about 1080 ng/mlto about 1500 ng/ml, from about 1090 ng/ml to about 1500 ng/ml, fromabout 1100 ng/ml to about 1500 ng/ml, from about 1110 ng/ml to about1500 ng/ml, from about 1120 ng/ml to about 1500 ng/ml, from about 1130ng/ml to about 1500 ng/ml, from about 1140 ng/ml to about 1500 ng/ml,from about 1150 ng/ml to about 1500 ng/ml, from about 1160 ng/ml toabout 1500 ng/ml, from about 1170 ng/ml to about 1500 ng/ml, from about1180 ng/ml to about 1500 ng/ml, from about 1190 ng/ml to about 1500ng/ml, from about 1200 ng/ml to about 1500 ng/ml, from about 1210 ng/mlto about 1500 ng/ml, from about 1220 ng/ml to about 1500 ng/ml, fromabout 1230 ng/ml to about 1500 ng/ml, from about 1240 ng/ml to about1500 ng/ml, from about 1250 ng/ml to about 1500 ng/ml, from about 1260ng/ml to about 1500 ng/ml, from about 1270 ng/ml to about 1500 ng/ml,from about 1280 ng/ml to about 1500 ng/ml, from about 1290 ng/ml toabout 1500 ng/ml, from about 1300 ng/ml to about 1500 ng/ml, from about1310 ng/ml to about 1500 ng/ml, from about 1320 ng/ml to about 1500ng/ml, from about 1330 ng/ml to about 1500 ng/ml, from about 1340 ng/mlto about 1500 ng/ml, from about 1350 ng/ml to about 1500 ng/ml, fromabout 1360 ng/ml to about 1500 ng/ml, from about 1370 ng/ml to about1500 ng/ml, from about 1380 ng/ml to about 1500 ng/ml, from about 1390ng/ml to about 1500 ng/ml, from about 1400 ng/ml to about 1500 ng/ml,from about 1410 ng/ml to about 1500 ng/ml, from about 1420 ng/ml toabout 1500 ng/ml, from about 1430 ng/ml to about 1500 ng/ml, from about1440 ng/ml to about 1500 ng/ml, from about 1450 ng/ml to about 1500ng/ml, from about 1460 ng/ml to about 1500 ng/ml, from about 1470 ng/mlto about 1500 ng/ml, from about 1480 ng/ml to about 1500 ng/ml, or fromabout 1490 ng/ml to about 1500 ng/ml.

In some embodiments, maximum concentration of the first therapeuticagent in blood (whole blood, plasma, or serum) (“Cmax”) of the subjectfollowing its administration to the subject is selected from 1000 ng/dl,about 1010 ng/dl, about 1020 ng/dl, about 1030 ng/dl, about 1040 ng/dl,about 1050 ng/dl, about 1060 ng/dl, about 1070 ng/dl, about 1080 ng/dl,about 1090 ng/dl, about 1100 ng/dl, about 1110 ng/dl, about 1120 ng/dl,about 1130 ng/dl, about 1140 ng/dl, about 1150 ng/dl, about 1160 ng/dl,about 1170 ng/dl, about 1180 ng/dl, about 1190 ng/dl, about 1200 ng/dl,about 1210 ng/dl, about 1220 ng/dl, about 1230 ng/dl, about 1240 ng/dl,about 1250 ng/dl, about 1260 ng/dl, about 1270 ng/dl, about 1280 ng/dl,about 1290 ng/dl, about 1300 ng/dl, about 1310 ng/dl, about 1320 ng/dl,about 1330 ng/dl, about 1340 ng/dl, about 1350 ng/dl, about 1360 ng/dl,about 1370 ng/dl, about 1380 ng/dl, about 1390 ng/dl, about 1400 ng/dl,about 1410 ng/dl, about 1420 ng/dl, about 1430 ng/dl, about 1440 ng/dl,about 1450 ng/dl, about 1460 ng/dl, about 1470 ng/dl, about 1480 ng/dl,and about 1490 ng/dl.

In some embodiments, maximum concentration of the first therapeuticagent in blood (whole blood, plasma, or serum) (“Cmax”) of the subjectfollowing its administration to the subject is selected from 1000 ng/ml,about 1010 ng/ml, about 1020 ng/ml, about 1030 ng/ml, about 1040 ng/ml,about 1050 ng/ml, about 1060 ng/ml, about 1070 ng/ml, about 1080 ng/ml,about 1090 ng/ml, about 1100 ng/ml, about 1110 ng/ml, about 1120 ng/ml,about 1130 ng/ml, about 1140 ng/ml, about 1150 ng/ml, about 1160 ng/ml,about 1170 ng/ml, about 1180 ng/ml, about 1190 ng/ml, about 1200 ng/ml,about 1210 ng/ml, about 1220 ng/ml, about 1230 ng/ml, about 1240 ng/ml,about 1250 ng/ml, about 1260 ng/ml, about 1270 ng/ml, about 1280 ng/ml,about 1290 ng/ml, about 1300 ng/ml, about 1310 ng/ml, about 1320 ng/ml,about 1330 ng/ml, about 1340 ng/ml, about 1350 ng/ml, about 1360 ng/ml,about 1370 ng/ml, about 1380 ng/ml, about 1390 ng/ml, about 1400 ng/ml,about 1410 ng/ml, about 1420 ng/ml, about 1430 ng/ml, about 1440 ng/ml,about 1450 ng/ml, about 1460 ng/ml, about 1470 ng/ml, about 1480 ng/ml,and about 1490 ng/ml.

In some embodiments, maximum concentration of the first therapeuticagent in blood (whole blood, plasma, or serum) (“Cmax”) of the subjectfollowing its administration to the subject is selected from about 85ng/dl, about 95 ng/dl, about 105 ng/dl, about 115 ng/dl, about 125ng/dl, about 135 ng/dl, about 145 ng/dl, about 155 ng/dl, about 165ng/dl, about 175 ng/dl, about 185 ng/dl, about 195 ng/dl, about 205ng/dl, about 215 ng/dl, about 225 ng/dl, about 235 ng/dl, about 245ng/dl, about 255 ng/dl, about 265 ng/dl, about 275 ng/dl, about 285ng/dl, about 295 ng/dl, about 305 ng/dl, about 315 ng/dl, about 325ng/dl, about 335 ng/dl, about 345 ng/dl, about 355 ng/dl, about 365ng/dl, about 375 ng/dl, about 385 ng/dl, about 395 ng/dl, about 405ng/dl, about 415 ng/dl, about 425 ng/dl, about 435 ng/dl, about 445ng/dl, about 455 ng/dl, about 465 ng/dl, about 475 ng/dl, about 485ng/dl, about 495 ng/dl, about 505 ng/dl, about 515 ng/dl, about 525ng/dl, about 535 ng/dl, about 545 ng/dl, about 555 ng/dl, about 565ng/dl, about 575 ng/dl, about 585 ng/dl, about 595 ng/dl, about 605ng/dl, about 615 ng/dl, about 625 ng/dl, about 635 ng/dl, about 645ng/dl, about 655 ng/dl, about 665 ng/dl, about 675 ng/dl, about 685ng/dl, about 695 ng/dl, about 705 ng/dl, about 715 ng/dl, about 725ng/dl, about 735 ng/dl, about 745 ng/dl, about 755 ng/dl, about 765ng/dl, about 775 ng/dl, about 785 ng/dl, about 795 ng/dl, about 805ng/dl, about 815 ng/dl, about 825 ng/dl, about 835 ng/dl, about 845ng/dl, about 855 ng/dl, about 865 ng/dl, about 875 ng/dl, about 885ng/dl, about 895 ng/dl, about 905 ng/dl, about 915 ng/dl, about 925ng/dl, about 935 ng/dl, about 945 ng/dl, about 955 ng/dl, about 965ng/dl, about 975 ng/dl, about 985 ng/dl, about 995 ng/dl, about 1005ng/dl, about 1015 ng/dl, about 1025 ng/dl, about 1035 ng/dl, about 1045ng/dl, about 1055 ng/dl, about 1065 ng/dl, about 1075 ng/dl, about 1085ng/dl, about 1095 ng/dl, about 1105 ng/dl, about 1115 ng/dl, about 1125ng/dl, about 1135 ng/dl, about 1145 ng/dl, about 1155 ng/dl, about 1165ng/dl, about 1175 ng/dl, about 1185 ng/dl, about 1195 ng/dl, about 1205ng/dl, about 1215 ng/dl, about 1225 ng/dl, about 1235 ng/dl, about 1245ng/dl, about 1255 ng/dl, about 1265 ng/dl, about 1275 ng/dl, about 1285ng/dl, about 1295 ng/dl, about 1305 ng/dl, about 1315 ng/dl, about 1325ng/dl, about 1335 ng/dl, about 1345 ng/dl, about 1355 ng/dl, about 1365ng/dl, about 1375 ng/dl, about 1385 ng/dl, about 1395 ng/dl, about 1405ng/dl, about 1415 ng/dl, about 1425 ng/dl, about 1435 ng/dl, about 1445ng/dl, about 1455 ng/dl, about 1465 ng/dl, about 1475 ng/dl, about 1485ng/dl, about 1495 ng/dl, and about 1500 ng/dl.

In some embodiments, maximum concentration of the first therapeuticagent in blood (whole blood, plasma, or serum) (“Cmax”) of the subjectfollowing its administration to the subject is selected from about 85ng/ml, about 95 ng/ml, about 105 ng/ml, about 115 ng/ml, about 125ng/ml, about 135 ng/ml, about 145 ng/ml, about 155 ng/ml, about 165ng/ml, about 175 ng/ml, about 185 ng/ml, about 195 ng/ml, about 205ng/ml, about 215 ng/ml, about 225 ng/ml, about 235 ng/ml, about 245ng/ml, about 255 ng/ml, about 265 ng/ml, about 275 ng/ml, about 285ng/ml, about 295 ng/ml, about 305 ng/ml, about 315 ng/ml, about 325ng/ml, about 335 ng/ml, about 345 ng/ml, about 355 ng/ml, about 365ng/ml, about 375 ng/ml, about 385 ng/ml, about 395 ng/ml, about 405ng/ml, about 415 ng/ml, about 425 ng/ml, about 435 ng/ml, about 445ng/ml, about 455 ng/ml, about 465 ng/ml, about 475 ng/ml, about 485ng/ml, about 495 ng/ml, about 505 ng/ml, about 515 ng/ml, about 525ng/ml, about 535 ng/ml, about 545 ng/ml, about 555 ng/ml, about 565ng/ml, about 575 ng/ml, about 585 ng/ml, about 595 ng/ml, about 605ng/ml, about 615 ng/ml, about 625 ng/ml, about 635 ng/ml, about 645ng/ml, about 655 ng/ml, about 665 ng/ml, about 675 ng/ml, about 685ng/ml, about 695 ng/ml, about 705 ng/ml, about 715 ng/ml, about 725ng/ml, about 735 ng/ml, about 745 ng/ml, about 755 ng/ml, about 765ng/ml, about 775 ng/ml, about 785 ng/ml, about 795 ng/ml, about 805ng/ml, about 815 ng/ml, about 825 ng/ml, about 835 ng/ml, about 845ng/ml, about 855 ng/ml, about 865 ng/ml, about 875 ng/ml, about 885ng/ml, about 895 ng/ml, about 905 ng/ml, about 915 ng/ml, about 925ng/ml, about 935 ng/ml, about 945 ng/ml, about 955 ng/ml, about 965ng/ml, about 975 ng/ml, about 985 ng/ml, about 995 ng/ml, about 1005ng/ml, about 1015 ng/ml, about 1025 ng/ml, about 1035 ng/ml, about 1045ng/ml, about 1055 ng/ml, about 1065 ng/ml, about 1075 ng/ml, about 1085ng/ml, about 1095 ng/ml, about 1105 ng/ml, about 1115 ng/ml, about 1125ng/ml, about 1135 ng/ml, about 1145 ng/ml, about 1155 ng/ml, about 1165ng/ml, about 1175 ng/ml, about 1185 ng/ml, about 1195 ng/ml, about 1205ng/ml, about 1215 ng/ml, about 1225 ng/ml, about 1235 ng/ml, about 1245ng/ml, about 1255 ng/ml, about 1265 ng/ml, about 1275 ng/ml, about 1285ng/ml, about 1295 ng/ml, about 1305 ng/ml, about 1315 ng/ml, about 1325ng/ml, about 1335 ng/ml, about 1345 ng/ml, about 1355 ng/ml, about 1365ng/ml, about 1375 ng/ml, about 1385 ng/ml, about 1395 ng/ml, about 1405ng/ml, about 1415 ng/ml, about 1425 ng/ml, about 1435 ng/ml, about 1445ng/ml, about 1455 ng/ml, about 1465 ng/ml, about 1475 ng/ml, about 1485ng/ml, about 1495 ng/ml, and about 1500 ng/ml.

In some embodiments of the method of treatment, the maximumconcentration of the first therapeutic agent in blood (whole blood,plasma, or serum) (“Cmax”) of the subject following its administrationto the subject ranges from about 85 ng/dl to 1500 ng/dl. In someembodiments, maximum concentration of the first therapeutic agent inblood (whole blood, plasma, or serum) (“Cmax”) of the subject followingits administration to the subject is selected from about 85 ng/dl toabout 1500 ng/dl, from about 95 ng/dl to about 1500 ng/dl, from about105 ng/dl to about 1500 ng/dl, from about 115 ng/dl to about 1500 ng/dl,from about 125 ng/dl to about 1500 ng/dl, from about 135 ng/dl to about1500 ng/dl, from about 145 ng/dl to about 1500 ng/dl, from about 155ng/dl to about 1500 ng/dl, from about 165 ng/dl to about 1500 ng/dl,from about 175 ng/dl to about 1500 ng/dl, from about 185 ng/dl to about1500 ng/dl, from about 195 ng/dl to about 1500 ng/dl, from about 205ng/dl to about 1500 ng/dl, from about 215 ng/dl to about 1500 ng/dl,from about 225 ng/dl to about 1500 ng/dl, from about 235 ng/dl to about1500 ng/dl, from about 245 ng/dl to about 1500 ng/dl, from about 255ng/dl to about 1500 ng/dl, from about 265 ng/dl to about 1500 ng/dl,from about 275 ng/dl to about 1500 ng/dl, from about 285 ng/dl to about1500 ng/dl, from about 295 ng/dl to about 1500 ng/dl, from about 305ng/dl to about 1500 ng/dl, from about 315 ng/dl to about 1500 ng/dl,from about 325 ng/dl to about 1500 ng/dl, from about 335 ng/dl to about1500 ng/dl, from about 345 ng/dl to about 1500 ng/dl, from about 355ng/dl to about 1500 ng/dl, from about 365 ng/dl to about 1500 ng/dl,from about 375 ng/dl to about 1500 ng/dl, from about 385 ng/dl to about1500 ng/dl, from about 395 ng/dl to about 1500 ng/dl, from about 405ng/dl to about 1500 ng/dl, from about 415 ng/dl to about 1500 ng/dl,from about 425 ng/dl to about 1500 ng/dl, from about 435 ng/dl to about1500 ng/dl, from about 445 ng/dl to about 1500 ng/dl, from about 455ng/dl to about 1500 ng/dl, from about 465 ng/dl to about 1500 ng/dl,from about 475 ng/dl to about 1500 ng/dl, from about 485 ng/dl to about1500 ng/dl, from about 495 ng/dl to about 1500 ng/dl, from about 505ng/dl to about 1500 ng/dl, from about 515 ng/dl to about 1500 ng/dl,from about 525 ng/dl to about 1500 ng/dl, from about 535 ng/dl to about1500 ng/dl, from about 545 ng/dl to about 1500 ng/dl, from about 555ng/dl to about 1500 ng/dl, from about 565 ng/dl to about 1500 ng/dl,from about 575 ng/dl to about 1500 ng/dl, from about 585 ng/dl to about1500 ng/dl, from about 595 ng/dl to about 1500 ng/dl, from about 605ng/dl to about 1500 ng/dl, from about 615 ng/dl to about 1500 ng/dl,from about 625 ng/dl to about 1500 ng/dl, from about 635 ng/dl to about1500 ng/dl, from about 645 ng/dl to about 1500 ng/dl, from about 655ng/dl to about 1500 ng/dl, from about 665 ng/dl to about 1500 ng/dl,from about 675 ng/dl to about 1500 ng/dl, from about 685 ng/dl to about1500 ng/dl, from about 695 ng/dl to about 1500 ng/dl, from about 705ng/dl to about 1500 ng/dl, from about 715 ng/dl to about 1500 ng/dl,from about 725 ng/dl to about 1500 ng/dl, from about 735 ng/dl to about1500 ng/dl, from about 745 ng/dl to about 1500 ng/dl, from about 755ng/dl to about 1500 ng/dl, from about 765 ng/dl to about 1500 ng/dl,from about 775 ng/dl to about 1500 ng/dl, from about 785 ng/dl to about1500 ng/dl, from about 795 ng/dl to about 1500 ng/dl, from about 805ng/dl to about 1500 ng/dl, from about 815 ng/dl to about 1500 ng/dl,from about 825 ng/dl to about 1500 ng/dl, from about 835 ng/dl to about1500 ng/dl, from about 845 ng/dl to about 1500 ng/dl, from about 855ng/dl to about 1500 ng/dl, from about 865 ng/dl to about 1500 ng/dl,from about 875 ng/dl to about 1500 ng/dl, from about 885 ng/dl to about1500 ng/dl, from about 895 ng/dl to about 1500 ng/dl, from about 905ng/dl to about 1500 ng/dl, from about 915 ng/dl to about 1500 ng/dl,from about 925 ng/dl to about 1500 ng/dl, from about 935 ng/dl to about1500 ng/dl, from about 945 ng/dl to about 1500 ng/dl, from about 955ng/dl to about 1500 ng/dl, from about 965 ng/dl to about 1500 ng/dl,from about 975 ng/dl to about 1500 ng/dl, from about 985 ng/dl to about1500 ng/dl, from about 995 ng/dl to about 1500 ng/dl, from about 1005ng/dl to about 1500 ng/dl, from about 1015 ng/dl to about 1500 ng/dl,from about 1025 ng/dl to about 1500 ng/dl, from about 1035 ng/dl toabout 1500 ng/dl, from about 1045 ng/dl to about 1500 ng/dl, from about1055 ng/dl to about 1500 ng/dl, from about 1065 ng/dl to about 1500ng/dl, from about 1075 ng/dl to about 1500 ng/dl, from about 1085 ng/dlto about 1500 ng/dl, from about 1095 ng/dl to about 1500 ng/dl, fromabout 1105 ng/dl to about 1500 ng/dl, from about 1115 ng/dl to about1500 ng/dl, from about 1125 ng/dl to about 1500 ng/dl, from about 1135ng/dl to about 1500 ng/dl, from about 1145 ng/dl to about 1500 ng/dl,from about 1155 ng/dl to about 1500 ng/dl, from about 1165 ng/dl toabout 1500 ng/dl, from about 1175 ng/dl to about 1500 ng/dl, from about1185 ng/dl to about 1500 ng/dl, from about 1195 ng/dl to about 1500ng/dl, from about 1205 ng/dl to about 1500 ng/dl, from about 1215 ng/dlto about 1500 ng/dl, from about 1225 ng/dl to about 1500 ng/dl, fromabout 1235 ng/dl to about 1500 ng/dl, from about 1245 ng/dl to about1500 ng/dl, from about 1255 ng/dl to about 1500 ng/dl, from about 1265ng/dl to about 1500 ng/dl, from about 1275 ng/dl to about 1500 ng/dl,from about 1285 ng/dl to about 1500 ng/dl, from about 1295 ng/dl toabout 1500 ng/dl, from about 1305 ng/dl to about 1500 ng/dl, from about1315 ng/dl to about 1500 ng/dl, from about 1325 ng/dl to about 1500ng/dl, from about 1335 ng/dl to about 1500 ng/dl, from about 1345 ng/dlto about 1500 ng/dl, from about 1355 ng/dl to about 1500 ng/dl, fromabout 1365 ng/dl to about 1500 ng/dl, from about 1375 ng/dl to about1500 ng/dl, from about 1385 ng/dl to about 1500 ng/dl, from about 1395ng/dl to about 1500 ng/dl, from about 1405 ng/dl to about 1500 ng/dl,from about 1415 ng/dl to about 1500 ng/dl, from about 1425 ng/dl toabout 1500 ng/dl, from about 1435 ng/dl to about 1500 ng/dl, from about1445 ng/dl to about 1500 ng/dl, from about 1455 ng/dl to about 1500ng/dl, from about 1465 ng/dl to about 1500 ng/dl, from about 1475 ng/dlto about 1500 ng/dl, from about 1485 ng/dl to about 1500 ng/dl, fromabout 1495 ng/dl to about 1500 ng/dl, and from about 1500 ng/dl to about1500 ng/dl.

In some embodiments of the method of treatment, the maximumconcentration of the first therapeutic agent in blood (whole blood,plasma, or serum) (“Cmax”) of the subject following its administrationto the subject ranges from about 85 ng/ml to 1500 ng/ml. In someembodiments, maximum concentration of the first therapeutic agent inblood (whole blood, plasma, or serum) (“Cmax”) of the subject followingits administration to the subject is selected from about 85 ng/ml toabout 1500 ng/ml, from about 95 ng/ml to about 1500 ng/ml, from about105 ng/ml to about 1500 ng/ml, from about 115 ng/ml to about 1500 ng/ml,from about 125 ng/ml to about 1500 ng/ml, from about 135 ng/ml to about1500 ng/ml, from about 145 ng/ml to about 1500 ng/ml, from about 155ng/ml to about 1500 ng/ml, from about 165 ng/ml to about 1500 ng/ml,from about 175 ng/ml to about 1500 ng/ml, from about 185 ng/ml to about1500 ng/ml, from about 195 ng/ml to about 1500 ng/ml, from about 205ng/ml to about 1500 ng/ml, from about 215 ng/ml to about 1500 ng/ml,from about 225 ng/ml to about 1500 ng/ml, from about 235 ng/ml to about1500 ng/ml, from about 245 ng/ml to about 1500 ng/ml, from about 255ng/ml to about 1500 ng/ml, from about 265 ng/ml to about 1500 ng/ml,from about 275 ng/ml to about 1500 ng/ml, from about 285 ng/ml to about1500 ng/ml, from about 295 ng/ml to about 1500 ng/ml, from about 305ng/ml to about 1500 ng/ml, from about 315 ng/ml to about 1500 ng/ml,from about 325 ng/ml to about 1500 ng/ml, from about 335 ng/ml to about1500 ng/ml, from about 345 ng/ml to about 1500 ng/ml, from about 355ng/ml to about 1500 ng/ml, from about 365 ng/ml to about 1500 ng/ml,from about 375 ng/ml to about 1500 ng/ml, from about 385 ng/ml to about1500 ng/ml, from about 395 ng/ml to about 1500 ng/ml, from about 405ng/ml to about 1500 ng/ml, from about 415 ng/ml to about 1500 ng/ml,from about 425 ng/ml to about 1500 ng/ml, from about 435 ng/ml to about1500 ng/ml, from about 445 ng/ml to about 1500 ng/ml, from about 455ng/ml to about 1500 ng/ml, from about 465 ng/ml to about 1500 ng/ml,from about 475 ng/ml to about 1500 ng/ml, from about 485 ng/ml to about1500 ng/ml, from about 495 ng/ml to about 1500 ng/ml, from about 505ng/ml to about 1500 ng/ml, from about 515 ng/ml to about 1500 ng/ml,from about 525 ng/ml to about 1500 ng/ml, from about 535 ng/ml to about1500 ng/ml, from about 545 ng/ml to about 1500 ng/ml, from about 555ng/ml to about 1500 ng/ml, from about 565 ng/ml to about 1500 ng/ml,from about 575 ng/ml to about 1500 ng/ml, from about 585 ng/ml to about1500 ng/ml, from about 595 ng/ml to about 1500 ng/ml, from about 605ng/ml to about 1500 ng/ml, from about 615 ng/ml to about 1500 ng/ml,from about 625 ng/ml to about 1500 ng/ml, from about 635 ng/ml to about1500 ng/ml, from about 645 ng/ml to about 1500 ng/ml, from about 655ng/ml to about 1500 ng/ml, from about 665 ng/ml to about 1500 ng/ml,from about 675 ng/ml to about 1500 ng/ml, from about 685 ng/ml to about1500 ng/ml, from about 695 ng/ml to about 1500 ng/ml, from about 705ng/ml to about 1500 ng/ml, from about 715 ng/ml to about 1500 ng/ml,from about 725 ng/ml to about 1500 ng/ml, from about 735 ng/ml to about1500 ng/ml, from about 745 ng/ml to about 1500 ng/ml, from about 755ng/ml to about 1500 ng/ml, from about 765 ng/ml to about 1500 ng/ml,from about 775 ng/ml to about 1500 ng/ml, from about 785 ng/ml to about1500 ng/ml, from about 795 ng/ml to about 1500 ng/ml, from about 805ng/ml to about 1500 ng/ml, from about 815 ng/ml to about 1500 ng/ml,from about 825 ng/ml to about 1500 ng/ml, from about 835 ng/ml to about1500 ng/ml, from about 845 ng/ml to about 1500 ng/ml, from about 855ng/ml to about 1500 ng/ml, from about 865 ng/ml to about 1500 ng/ml,from about 875 ng/ml to about 1500 ng/ml, from about 885 ng/ml to about1500 ng/ml, from about 895 ng/ml to about 1500 ng/ml, from about 905ng/ml to about 1500 ng/ml, from about 915 ng/ml to about 1500 ng/ml,from about 925 ng/ml to about 1500 ng/ml, from about 935 ng/ml to about1500 ng/ml, from about 945 ng/ml to about 1500 ng/ml, from about 955ng/ml to about 1500 ng/ml, from about 965 ng/ml to about 1500 ng/ml,from about 975 ng/ml to about 1500 ng/ml, from about 985 ng/ml to about1500 ng/ml, from about 995 ng/ml to about 1500 ng/ml, from about 1005ng/ml to about 1500 ng/ml, from about 1015 ng/ml to about 1500 ng/ml,from about 1025 ng/ml to about 1500 ng/ml, from about 1035 ng/ml toabout 1500 ng/ml, from about 1045 ng/ml to about 1500 ng/ml, from about1055 ng/ml to about 1500 ng/ml, from about 1065 ng/ml to about 1500ng/ml, from about 1075 ng/ml to about 1500 ng/ml, from about 1085 ng/mlto about 1500 ng/ml, from about 1095 ng/ml to about 1500 ng/ml, fromabout 1105 ng/ml to about 1500 ng/ml, from about 1115 ng/ml to about1500 ng/ml, from about 1125 ng/ml to about 1500 ng/ml, from about 1135ng/ml to about 1500 ng/ml, from about 1145 ng/ml to about 1500 ng/ml,from about 1155 ng/ml to about 1500 ng/ml, from about 1165 ng/ml toabout 1500 ng/ml, from about 1175 ng/ml to about 1500 ng/ml, from about1185 ng/ml to about 1500 ng/ml, from about 1195 ng/ml to about 1500ng/ml, from about 1205 ng/ml to about 1500 ng/ml, from about 1215 ng/mlto about 1500 ng/ml, from about 1225 ng/ml to about 1500 ng/ml, fromabout 1235 ng/ml to about 1500 ng/ml, from about 1245 ng/ml to about1500 ng/ml, from about 1255 ng/ml to about 1500 ng/ml, from about 1265ng/ml to about 1500 ng/ml, from about 1275 ng/ml to about 1500 ng/ml,from about 1285 ng/ml to about 1500 ng/ml, from about 1295 ng/ml toabout 1500 ng/ml, from about 1305 ng/ml to about 1500 ng/ml, from about1315 ng/ml to about 1500 ng/ml, from about 1325 ng/ml to about 1500ng/ml, from about 1335 ng/ml to about 1500 ng/ml, from about 1345 ng/mlto about 1500 ng/ml, from about 1355 ng/ml to about 1500 ng/ml, fromabout 1365 ng/ml to about 1500 ng/ml, from about 1375 ng/ml to about1500 ng/ml, from about 1385 ng/ml to about 1500 ng/ml, from about 1395ng/ml to about 1500 ng/ml, from about 1405 ng/ml to about 1500 ng/ml,from about 1415 ng/ml to about 1500 ng/ml, from about 1425 ng/ml toabout 1500 ng/ml, from about 1435 ng/ml to about 1500 ng/ml, from about1445 ng/ml to about 1500 ng/ml, from about 1455 ng/ml to about 1500ng/ml, from about 1465 ng/ml to about 1500 ng/ml, from about 1475 ng/mlto about 1500 ng/ml, from about 1485 ng/ml to about 1500 ng/ml, fromabout 1495 ng/ml to about 1500 ng/ml, and from about 1500 ng/ml to about1500 ng/ml.

In some embodiments of the method the total drug exposure over time,measured as the area under the curve (“AUC”) of a plot of theconcentration of the drug in blood (whole blood, plasma, or serum) ofthe subject following administration of the drug against time afteradministration of the drug ranges from about 150 ng hr/ml to about 8000ng hr/ml. In some embodiments, AUC is less than 8000 ng hr/ml and isgreater than or equal to 150 ng hr/ml.

In some embodiments of the method the total drug exposure over time,measured as the area under the curve (“AUC”) of a plot of theconcentration of the drug in blood (whole blood, plasma, or serum) ofthe subject following administration against time is an AUC of fromabout 100 ng hr/ml to about 8000 ng hr/ml, from about 150 ng hr/ml toabout 8000 ng hr/ml, from about 200 ng hr/ml to about 8000 ng hr/ml,from about 400 ng hr/ml to about 8000 ng hr/ml, from about 600 ng hr/mlto about 8000 ng hr/ml, from about 800 ng hr/ml to about 8000 ng hr/ml,from about 1000 ng hr/ml to about 8000 ng hr/ml, from about 1200 nghr/ml to about 8000 ng hr/ml, from about 1400 ng hr/ml to about 8000 nghr/ml, from about 1600 ng hr/ml to about 8000 ng hr/ml, from about 1800ng hr/ml to about 8000 ng hr/ml, from about 2000 ng hr/ml to about 8000ng hr/ml, from about 2200 ng hr/ml to about 8000 ng hr/ml, from about2400 ng hr/ml to about 8000 ng hr/ml, from about 2600 ng hr/ml to about8000 ng hr/ml, from about 2800 ng hr/ml to about 8000 ng hr/ml, fromabout 3000 ng hr/ml to about 8000 ng hr/ml, from about 3200 ng hr/ml toabout 8000 ng hr/ml, from about 3400 ng hr/ml to about 8000 ng hr/ml,from about 3600 ng hr/ml to about 8000 ng hr/ml, from about 3800 nghr/ml to about 8000 ng hr/ml, from about 4000 ng hr/ml to about 8000 nghr/ml, from about 4200 ng hr/ml to about 8000 ng hr/ml, from about 4400ng hr/ml to about 8000 ng hr/ml, from about 4600 ng hr/ml to about 8000ng hr/ml, from about 4800 ng hr/ml to about 8000 ng hr/ml, from about5000 ng hr/ml to about 8000 ng hr/ml, from about 5200 ng hr/ml to about8000 ng hr/ml, from about 5400 ng hr/ml to about 8000 ng hr/ml, fromabout 5600 ng hr/ml to about 8000 ng hr/ml, from about 5800 ng hr/ml toabout 8000 ng hr/ml, from about 6000 ng hr/ml to about 8000 ng hr/ml,from about 6200 ng hr/ml to about 8000 ng hr/ml, from about 6400 nghr/ml to about 8000 ng hr/ml, from about 6600 ng hr/ml to about 8000 nghr/ml, from about 6800 ng hr/ml to about 8000 ng hr/ml, from about 7000ng hr/ml to about 8000 ng hr/ml, from about 7200 ng hr/ml to about 8000ng hr/ml, from about 7400 ng hr/ml to about 8000 ng hr/ml, from about7600 ng hr/ml to about 8000 ng hr/ml, or from about 7800 ng hr/ml toabout 8000 ng hr/ml.

In some embodiments of the method the total drug exposure over time,measured as the area under the curve (“AUC”) of a plot of theconcentration of the drug in blood (whole blood, plasma, or serum) ofthe subject following administration against time is an AUC of fromabout 100 ng hr/ml to about 8000 ng hr/ml, from about 150 ng hr/ml toabout 7800 ng hr/ml, from about 150 ng hr/ml to about 7600 ng hr/ml,from about 150 ng hr/ml to about 7400 ng hr/ml, from about 150 ng hr/mlto about 7200 ng hr/ml, from about 150 ng hr/ml to about 7000 ng hr/ml,from about 150 ng hr/ml to about 6800 ng hr/ml, from about 150 ng hr/mlto about 6600 ng hr/ml, from about 150 ng hr/ml to about 6400 ng hr/ml,from about 150 ng hr/ml to about 6200 ng hr/ml, from about 150 ng hr/mlto about 6000 ng hr/ml, from about 150 ng hr/ml to about 5800 ng hr/ml,from about 150 ng hr/ml to about 5600 ng hr/ml, from about 150 ng hr/mlto about 5400 ng hr/ml, from about 150 ng hr/ml to about 5200 ng hr/ml,from about 1500 ng hr/ml to about 5000 ng hr/ml, from about 1500 nghr/ml to about 4800 ng hr/ml, from about 150 ng hr/ml to about 4600 nghr/ml, from about 150 ng hr/ml to about 4400 ng hr/ml, from about 150 nghr/ml to about 4200 ng hr/ml, from about 150 ng hr/ml to about 4000 nghr/ml, from about 150 ng hr/ml to about 3800 ng hr/ml, from about 150 nghr/ml to about 3600 ng hr/ml, from about 150 ng hr/ml to about 3400 nghr/ml, from about 150 ng hr/ml to about 3200 ng hr/ml, from about 150 nghr/ml to about 3000 ng hr/ml, from about 1500 ng hr/ml to about 2800 nghr/ml, from about 150 ng hr/ml to about 2600 ng hr/ml, from about 150 nghr/ml to about 2400 ng hr/ml, from about 150 ng hr/ml to about 2200 nghr/ml, from about 150 ng hr/ml to about 2000 ng hr/ml, from about 150 nghr/ml to about 1800 ng hr/ml, from about 150 ng hr/ml to about 1600 nghr/ml, from about 150 ng hr/ml to about 1400 ng hr/ml, from about 150 nghr/ml to about 1200 ng hr/ml, from about 150 ng hr/ml to about 1000 nghr/ml, from about 150 ng hr/ml to about 800 ng hr/ml, from about 150 nghr/ml to about 600 ng hr/ml, from about 150 ng hr/ml to about 400 nghr/ml, from about 150 ng hr/ml to about 200 ng hr/ml, or from about 100ng hr/ml to about 200 ng hr/ml.

In some embodiments of the method the total drug exposure over time,measured as the area under the curve (“AUC”) of a plot of theconcentration of the drug in blood (whole blood, plasma, or serum) ofthe subject following administration against time is selected from about100 ng hr/ml, about 150 ng hr/ml, about 200 ng hr/ml, about 400 nghr/ml, about 600 ng hr/ml, about 800 ng hr/ml, about 1000 ng hr/ml,about 1200 ng hr/ml, about 1400 ng hr/ml, about 1600 ng hr/ml, about1800 ng hr/ml, about 2000 ng hr/ml, about 2200 ng hr/ml, about 2400 nghr/ml, about 2600 ng hr/ml, about 2800, about 3000 ng hr/ml, about 3200ng hr/ml, about 3400 ng hr/ml, about 3600 ng hr/ml, about 3800 ng hr/ml,about 4000 ng hr/ml, about 4200 ng hr/ml, about 4400 ng hr/ml, about46000 ng hr/ml, about 4800 ng hr/ml, about 5000 ng hr/ml, about 5200 nghr/ml, about 5400 ng hr/ml, about 5600 ng hr/ml, about 5800 ng hr/ml,about 6000 ng hr/ml, about 6200 ng hr/ml, about 6400 ng hr/ml, about6600 ng hr/ml, about 6800 ng hr/ml, about 7000 ng hr/ml, about 7200 nghr/ml, about 7400 ng hr/ml, about 7600 ng hr/ml, about 7800 ng hr/ml,and about 8000 ng hr/ml.

In another aspect, the present invention provides a method of treatment,or use of the composition to treat a disease state, which comprisesadministering to a subject in need of such treatment a combination of afirst therapeutic agent and a second therapeutic agent, the methodcomprising:

(i) administering to the subject the first therapeutic agent includingcompound (1):

or a pharmaceutically acceptable salt thereof;

(ii) monitoring level of compound (1) or a pharmaceutically acceptablesalt thereof or a metabolite thereof in the subject usingpharmacokinetic profiling; and

(iii) administering the second therapeutic agent conditional on thelevel of the first therapeutic agent in the subject. In some embodimentsof the method, the monitoring step includes constructing apharmacokinetic profile of compound (1) or a pharmaceutically acceptablesalt thereof or a metabolite thereof for the subject usingconcentrations of compound (1) or a pharmaceutically acceptable saltthereof or a metabolite thereof in at least two samples obtained fromthe subject at time points suitable to construct a pharmacokineticprofile. In some embodiments of the method, the at least two samples arecollected at point-of-care or point of use by sampling or self-samplingon point-of-care devices or point of use devices or on matrices suitablefor storage of the at least two samples prior to quantitation ofcompound (1) or a pharmaceutically acceptable salt thereof or ametabolite by a laboratory. In some embodiments of the method, eachpoint-of-care devices or point of use devices is capable of quantitatingcompound (1) or a pharmaceutically acceptable salt thereof or ametabolite. In some embodiments of the method, the pharmacokineticprofile includes pharmacokinetic parameters suitable for guiding dosingof compound (1) or a pharmaceutically acceptable salt thereof for thesubject. In some embodiments of the method, the at least two samplesinclude from 2-12 samples. In some embodiments of the method, the atleast two samples are collected over a time period of up to 8 hours, upto 24 hours, up to 48 hours, or up to 72 hours. In some embodiments ofthe method, the pharmacokinetic parameters include at least oneparameter selected from the group consisting of AUC, AUCinf, Tmax, Cmax,time above threshold, steady state concentration, absorption rate,clearance rate, distribution rate, terminal T-1/2 or parameters drawnfrom noncompartmental pharmacokinetic (PK) or compartmental PK analysis,including physiological model-based compartmental PK analysis. In someembodiments of the method, the method of treatment further comprisesgenerating a report including the pharmacokinetic profile of thesubject. In some embodiments of the method, the report includes arecommendation regarding dosing based on the pharmacokinetic profile ofthe subject. In some embodiments of the method, a reduction in dosage ofcompound (1) or a pharmaceutically acceptable salt thereof is indicatedto reduce risk of toxicity based on one or more pharmacokineticparameters. In some embodiments of the method, the reduction in dosageof compound (1) or a pharmaceutically acceptable salt thereof isindicated based on time above threshold, wherein the threshold is thedrug concentration above which toxicity occurs, or one or more of AUC,AUCinf, mean residence time (MRT), exponentials defining thepharmacokinetic profile, volume of distribution at steady state (Vss),volume of distribution during the terminal phase (Vz) or combination ofa group of pharmacokinetic variable to adequately describe thepharmacokinetic profile. In some embodiments of the method, a doseadjustment of compound (1) or a pharmaceutically acceptable salt thereofis indicated to increase efficacy based on one or more pharmacokineticparameters. In some embodiments of the method, an increase in dosage ofcompound (1) or a pharmaceutically acceptable salt thereof is indicatedbased on one or more of AUC, AUCinf, MRT, exponentials defining thepharmacokinetic profile, steady state volume (Vss) of distribution,volume of distribution during the terminal phase (Vz) or combination ofa group of pharmacokinetic variables to adequately describe thepharmacokinetic profile. In some embodiments of the method, the dose ofcompound (1) or a pharmaceutically acceptable salt thereof is adjustedto within 5% to 25% of a desired target value. In some embodiments ofthe method, each of the at least two samples is applied to thepoint-of-care device or the point of use device for determining theconcentration of the compound (1) or a pharmaceutically acceptable saltthereof or a metabolite thereof, wherein the point-of-care device or thepoint of use device comprises a lateral flow strip having a constructionand composition such that an application of one or more of the at leasttwo samples to the lateral flow strip causes a fraction of the drug inthe sample to bind to with a component of the lateral flow strip suchthat a detectable signal proportional to the concentration of the drugin the applied sample is produced. In some embodiments of the method,the at least two samples are applied to matrices suitable for storage ofthe at least two samples prior to quantitation by a laboratory. In someembodiments of the method, the at least two samples are stored as driedblood spots. In some embodiments of the method, drug concentrations aremeasured by ELISA, LC MS MS, LC UV or LCMS. In some embodiments of themethod, the pharmacokinetic parameters include at least one of steadystate concentration, absorption, and terminal T1/2. In some embodimentsof the method, at least one of the at least two samples is whole blood.

V. TNF-RELATED APOPTOSIS-INDUCING LIGAND (“TRAIL”)

TRAIL protein can be assayed in a test sample obtained from a subject todetect TRAIL expression induced by compound (1) or a pharmaceuticallyacceptable salt thereof. Immunoassay methods can be used to assay TRAILin a sample, including, but not limited to, enzyme-linked immunosorbentassay (ELISA), enzyme-linked immunofiltration assay (ELIFA), flowcytometry, immunoblot, immunoprecipitation, immunohistochemistry,immunocytochemistry, luminescent immunoassay (LIA), fluorescentimmunoassay (FIA), and radioimmunoassay. Assay methods may be used toobtain qualitative and/or quantitative results. Specific details ofsuitable assay methods for both qualitative and quantitative assay of asample are described in standard references, illustratively including E.Harlow and D. Lane, Antibodies: A Laboratory Manual, Cold Spring HarborLaboratory Press, 1988; F. Breitling and S. Diibel, RecombinantAntibodies, John Wiley & Sons, New York, 1999; H. Zola, MonoclonalAntibodies: Preparation and Use of Monoclonal Antibodies and EngineeredAntibody Derivatives, Basics: From Background to Bench, BIOS ScientificPublishers, 2000; B. K. C. Lo, Antibody Engineering: Methods andProtocols, Methods in Molecular Biology, Humana Press, 2003; F. M.Ausubel et al., Eds., Short Protocols in Molecular Biology, CurrentProtocols, Wiley, 2002; S. Klussman, Ed., The Aptamer Handbook:Functional Oligonucleotides and Their Applications, Wiley, 2006;Ormerod, M. G., Flow Cytometry: a practical approach, Oxford UniversityPress, 2000; Givan, A. L., Flow Cytometry: first principles, Wiley, NewYork, 2001; Gorczyca, W., Flow Cytometry in Neoplastic Hematology:morphologic-immunophenotypic correlation, Taylor & Francis, 2006;Crowther, J. R., The ELISA Guidebook (Methods in Molecular Biology),Humana Press, 2000; Wild, D., The Immunoassay Handbook, 3rd Edition,Elsevier Science, 2005. and J. Sambrook and D. W. Russell, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, 3rdEd., 2001.

Examples of protocols for assaying and analyzing a sample for TRAIL forthe purpose of detection of an effect of a pharmaceutical composition ofthe present invention are described in U.S. Patent Application No.2012/0276088 to Wafik S. El-deiry et al., which is incorporated byreference herein in its entirety.

In some embodiments of the present invention, assays for TRAIL are usedto monitor a subject. Thus, for example, a test sample is obtained fromthe subject before treatment with a pharmaceutical composition of thepresent invention and at one or more times during and/or followingtreatment in order to assess effectiveness of the treatment. In afurther example, a test sample is obtained from the subject at varioustimes in order to assess the course or progress of disease or healing.In one embodiment, death receptors can also be analyzed from circulatingtumor cells to see if the administration of compound (1) or apharmaceutically acceptable salt thereof increases the amount or type ofdeath receptors.

Cancers treated using methods and compositions described herein arecharacterized by abnormal cell proliferation including, but not limitedto, pre-neoplastic hyperproliferation, cancer in-situ, neoplasms andmetastasis. Methods and compositions of the present invention can beused for prophylaxis as well as amelioration of signs and/or symptoms ofcancer. The terms “treating” and “treatment” used to refer to treatmentof a cancer in a subject include: preventing, inhibiting or amelioratingthe cancer in the subject, such as slowing progression of the cancerand/or reducing or ameliorating a sign or symptom of the cancer.Examples of cancers treated using methods and compositions of thepresent invention include, but are not limited to, breast cancer, CNScancers, colon cancer, ovarian cancer, prostate cancer, leukemia, lungcancer, and lymphoma.

VI. MULTIMODAL THERAPEUTIC METHODS

In one aspect, the present invention is directed to multimodaltherapeutic methods in which administration of compound (1) or apharmaceutically acceptable salt thereof to a subject in need of suchtreatment is supplemented by administration of other therapeuticmodalities. In one embodiment, the multimodal therapeutic method of thepresent invention comprises administering to a subject a pharmaceuticalcomposition comprising the compound (1) or a pharmaceutically acceptablesalt thereof in conjunction with radiation therapy or after radiation isdetermined to not have been efficacious. In one embodiment, themultimodal therapeutic method of the present invention comprisesadministering to a subject a pharmaceutical composition comprisingcompound (1) or a pharmaceutically acceptable salt thereof inconjunction with radiation therapy, wherein the pharmaceuticalcomposition comprising compound (1) or a pharmaceutically acceptablesalt thereof and the radiation therapy are administered concurrently orsequentially in any order. In one embodiment, the multimodal therapeuticmethod comprises administering to a subject a pharmaceutical compositioncomprising compound (1) or a pharmaceutically acceptable salt thereof inconjunction with radiation therapy in a sequential arrangement. In oneembodiment, the multimodal therapeutic method comprises administering toa subject in need of such treatment a pharmaceutical compositioncomprising compound (1) or a pharmaceutically acceptable salt thereofconcurrently with radiation therapy. In one embodiment, the multimodaltherapeutic method of the present invention is used for the treatment ofcancer. In one embodiment, the multimodal therapeutic method includesadministering to a cancer subject in need of such treatment apharmaceutical composition comprising compound (1) or a pharmaceuticallyacceptable salt thereof and irradiating cancer cells with a radiationbeam. In one embodiment, the multimodal therapeutic method uses thetechnique of conformal radiotherapy (CRT) to deliver a dose volumehistogram (DVH) prescribed to a cancer subject. In one embodiment, themultimodal therapeutic method uses the technique of intensity modulatedradiation therapy (IMRT) to deliver radiation to cancer cells. In oneembodiment, the multimodal therapeutic method uses a techniquescompensates for motion of tumors in the subject during treatment (e.g.,where doses of radiation must be administered to a thoracic tumor whichmoves as the patient breathes). In one embodiment, the multimodaltherapeutic method use Four Dimensional Computed Tomography (4D CT)scanning techniques to adjust the delivered radiation field tocompensate for tumor motion over the breathing cycle.

Any suitable type of radiation, including gamma radiation which is givenfractionated, IMRT (intensity modulated radiation therapy), gamma knife,proton therapy and brachytherapy can be used with the multimodaltherapeutic method of the present invention. Radiation therapy andcompound (1) or a pharmaceutically acceptable salt thereof can be usedto treat brain tumors such as glioblastoma or disease that hasmetastasized to the brain from lung cancer. The multimodal therapeuticmethod of the present invention can be used to treat lung cancer,pancreatic cancer, rectal cancer, breast cancer, sarcoma, prostatecancer, gynecological malignancies, and lymphoma. The gamma knife isused frequently to treat brain metastases. In one embodiment, themultimodal therapeutic method of the present invention includes use ofproton therapy to treat cancer, including brain tumors, prostate cancerand any tumor proximate vital organs where it is very important tominimize toxicity to nearby normal tissue.

In one embodiment, the multimodal therapeutic method of the presentinvention eliminates minimal residual disease without adding to anytoxicity resulting from treatment compound (1) or a pharmaceuticallyacceptable salt thereof. In one embodiment, the multimodal therapeuticmethod of the present invention improves prognosis and/or reducesadverse side-effects associated with a disease state or condition in asubject undergoing treatment.

VII. SYNTHESIS OF A SALT OF COMPOUND (1) AND RELATED ANALOGS

The compound represented by the above compound (1) can be prepared bythe synthetic process illustrated in Scheme 1 below.

In one embodiment, the process for making dihydrochloride salt ofcompound (1) commences with the intermediary compound of (3), also knownas N-Benzyl-3-carbomethoxy-4-piperidone hydrochloride, which iscommercially available. In one embodiment, the synthetic processincludes neutralizing the intermediary compound of (3) with a base(Step 1) to produce the compound of (4), a free base. In one embodiment,the synthetic process includes neutralizing the intermediary compound of(3) with an inorganic base to produce the compound of (4). In oneembodiment, the synthetic process includes neutralizing the intermediarycompound of (3) with an organic base to produce the compound of (4). Inone embodiment, the intermediary compound of (3) is neutralized in thepresence of an alcohol. In one such embodiment, the intermediarycompound of (3) is neutralized in the presence of n-butanol. In oneembodiment, the intermediary compound of (3) is neutralized in thepresence of at least one organic solvent. In one such embodiment, theintermediary compound of (3) is neutralized in the presence of n-butanoland/or ethyl acetate. In one embodiment, the intermediary compound of(3) is neutralized in the presence of a base and at least one organicsolvent. In one such embodiment, the intermediary compound of (3) isneutralized in the presence of NaHCO₃ and n-butanol. In one embodiment,the intermediary compound of (3) is neutralized in the presence ofn-butanol and triethyl amine (Et3N).

In one embodiment, the synthetic process includes reacting the compoundof (4) with the compound of (5) (Step 2) to produce intermediarycompound of (1). In one embodiment, the reaction in Step 2 includesheating the compound of (4) with the compound of (5). In one embodiment,the reaction in Step 2 includes refluxing heating the compound of (4)and the compound of (5) in the presence of a solvent. In one embodiment,the reaction in Step 2 includes use of Dean-stark trap to remove waterand/or methanol (MeOH) formed in the reaction.

In one embodiment, the synthetic process includes forming adihydrochloride salt of the compound of (1) (Step 3). In one embodiment,the reaction in Step 3 includes treating compound of (1) with HCl indioxane. In one embodiment, the reaction in Step 3 includes treatingcompound (3) with 4N HCl in dioxane.

In one embodiment, the synthetic process optionally includesrecrystallization of the di-salt of compound (1).

In one preferred embodiment, the synthetic process for the preparationof the di-hydrochloride salt of compound (1) is as illustrated in thefollowing Scheme 2.

VIII. DERIVATIVES AND ANALOGS OF AND SALTS OF COMPOUND (1) AND RELATEDCOMPOUNDS

In one aspect, the present invention provides analogs and related saltsof compound (1) and processes of making the same. Persons skilled in theart will understand that the same general principles and conceptsdescribed above in conjunction with compound (1) and salts thereof,including principles and concepts related to methods and pharmaceuticalcompositions, apply with equal force to derivatives and analogs of andsalts of compound (1) and salts thereof.

In one embodiment, the compounds related to compound (1) have thestructure of compound (10):

wherein R₁ and R₂ independently represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,heteroaryl, acyl, and heterocycle radicals. In another embodiment, thecompounds related to compound (1) have the structure of compound (10),wherein R₁ and R₂ are independently selected from the group consistingof H, C₁₋₄alkyl, C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In stillanother embodiment, the compounds related to compound (1) have thestructure of compound (10), wherein R₁ and R₂ are independently selectedfrom the group consisting of H, CH₃, CH₂Ph, CH₂-((2-Cl)-Ph),CH₂-(2-thienyl), CH₂CH₂Ph, CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-diF-Ph), CH₂-((2-CH₃)-Ph), CH₂CHOHPh, and (CH₂)₃CO-4F-Ph. In someembodiments, when R₁ represents CH₂Ph, R₂ does not representCH₂-((2-CH₃)-Ph.

As illustrated in Schemes 3 and 4, compound (10) can be synthesizedstarting either with methyl 1-R₁₋₄-oxo-3-piperidinecarboxylate (6) or byreacting compound (12) with compound (6).

Scheme 3 illustrates the synthesis of compound (10) starting fromcompound (6). In one embodiment, as illustrated in Scheme 3, compound(6) was converted into 4-amino-3-pyridinecarboxylic acid ester methylester (7) (or methyl4-amino-1-R₁-1,2,5,6-tetrahydro-3-pyridinecarboxylate) by a reactionwith ammonia. In one embodiment, compound (7) (or4-amino-3-pyridinecarboxylic acid ester methyl ester (7)) was treatedwith 2-(Methylsulfanyl)-4,5-dihydro-1H-imidazole (8) to make compound(9), which when alkylated R₂X, wherein R₂ is as defined above and X is ahalogen or an equivalent leaving group, produced compound (10) withdifferent values for the R₂ substituent.

Scheme 4 illustrates the synthesis of compound (10) starting fromcompound (6) and compound (12). In one embodiment, as illustrated inScheme 4, compound (12) is prepared from compound (8). In oneembodiment, compound (12) was treated with compound (6) to producecompound (10) with different values for the R₂ substituent.

Scheme 5 illustrates the synthesis of compound (10) starting fromcompound (11). In one embodiment, as illustrated in Scheme 5, compound(11), having a nitrogen protecting group (P) at the N atom at ringposition 7, was first deprotected and then akylated with R₁X, wherein R₁is as defined above and X is a halogen or an equivalent leaving group,to produce compound (10) with different values for the R₁ substituent.In some embodiments compound (10) can be prepared as a salt, for examplea 2TFA salt or 2HCl salt. In some embodiments, compound (10) can beprepared as a 2HCl salt by following a scheme analagous to Scheme 2described above.

Examples of Compound (10)

No. ONC Number R₁ R₂ 1 ONC201 CH₂Ph CH₂-((2-CH₃)—Ph) 13 CH₂Ph CH₃ 14ONC902 CH₂Ph CH₂-((2-Cl)—Ph) 15 ONC903 CH₂Ph CH₂-(2-thienyl) 16 ONC904CH₂Ph CH₂CH₂Ph 17 ONC905 CH₂Ph CH₂CH₂(4-N- benzyl-piperazine) 18 ONC906CH₂Ph CH₂-(2,4-di F—Ph) 19 ONC907 H CH₂-((2-CH₃)—Ph) 20 ONC908 CH₃CH₂-((2-CH₃)—Ph) 21 ONC909 CH₂CH₂Ph CH₂-((2-CH₃)—Ph) 22 CH₂CH₂-(4-N-CH₂-((2-CH₃)—Ph) benzyl-piperizine) 23 CH₂CHOHPh CH₂-((2-CH₃)—Ph) 24(CH₂)₃CO—4F—Ph CH₂-((2-CH₃)—Ph) 32 ONC910 (PV CH₂CH₂NHCOOC(CH₃)₃CH₂-((2-CH₃)—Ph) 03171) 33 ONC911 (PV CH₂CH₂CH₂NH₂ CH₂-((2-CH₃)—Ph)03172)

In one embodiment, the analogs have the structure of compound (25):

wherein Y represents NR₄ or O, and wherein R₁, R₂, R₃, and R₄independently represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl,hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy,aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl,arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, andheterocycle radicals. In some embodiments, R₁, R₂, R₃, and R₄ areoptionally substituted. In some embodiments, some or all hydrogens inR₁, R₂, R₃, and R₄ may be substituted by deuterium. In otherembodiments, the analogs have the structure of compound (25), whereinR₁, R₂, R₃, and R₄ are independently selected from the group consistingof H, C₁₋₄alkyl, C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (25), whereinR₁, R₂, R₃, and R₄ are independently selected from the group consistingof H, CH₃, CH₂Ph, CH₂-((2-Cl)-Ph), CH₂-(2-thienyl), CH₂CH₂Ph,CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-di F-Ph), CH₂-((2-CH₃)-Ph),CH₂CHOHPh, and (CH₂)₃CO-4F-Ph.

In one embodiment, the analogs have the structure of compound (26):

wherein R₁ and R₂, independently represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,heteroaryl, acyl, and heterocycle radicals. In some embodiments, R₁ andR₂ are optionally substituted. In some embodiments, some or allhydrogens in R₁ and R₂ may be substituted by deuterium. In otherembodiments, the analogs have the structure of compound (26), wherein R₁and R₂ are independently selected from the group consisting of H,C₁₋₄alkyl, C₁-4alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (26), wherein R₁and R₂ are independently selected from the group consisting of H, CH₃,CH₂Ph, CH₂-((2-Cl)-Ph), CH₂-(2-thienyl), CH₂CH₂Ph,CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-di F-Ph), CH₂-(2,3,4-tri F-Ph),CH₂-(2,3,4,5-quadra F-Ph), CH₂-(penta F-Ph) CH₂-((2-CH₃)-Ph), CH₂CHOHPh,and (CH₂)₃CO-4F-Ph. In still other embodiments, the analogs have thestructure of compound (26), wherein R₁ and R₂ are independently selectedfrom the group consisting of C₆H₄(CH₃), C₆H₃(CH₃)₂, C₆H₂(CH₃)₃,C₆H(CH₃)₄, C₆(CH₃)₅, CH₂—C₆H₄(CH₃), CH₂—C₆H₃(CH₃)₂, CH₂—C₆H₂(CH₃)₃,CH₂—C₆H(CH₃)₄, CH₂—C₆(CH₃)₅. In still other embodiments, the analogshave the structure of compound (26), wherein R₁ and R₂ are independentlyselected from the group consisting of C₆H₄(OH), C₆H₃(OH)₂, C₆H₂(OH)₃,C₆H(OH)₄, C₆(OH)₅, CH₂—C₆H₄(OH), CH₂—C₆H₃(OH)₂, CH₂—C₆H₂(OH)₃,CH₂—C₆H(OH)₄, CH₂—C₆(OH)₅.

In one embodiment, the analogs have the structure of compound (27):

wherein R₁ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl,hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, aralkoxy,aralkylthio, alkanoyl, mercapto, alkylthio, arylthio, alkylsulfinyl,arylsulfinyl, alkylsulfonyl, arylsulfonyl, heteroaryl, acyl, andheterocycle radicals. In some embodiments, R₁ is optionally substituted.In some embodiments, some or all hydrogens in R₁ may be substituted bydeuterium. In other embodiments, the analogs have the structure ofcompound (27), wherein R₁ is selected from the group consisting of H,C₁₋₄alkyl, C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (27), wherein R₁is selected from the group consisting of H, CH₃, CH₂Ph, CH₂-((2-Cl)-Ph),CH₂-(2-thienyl), CH₂CH₂Ph, CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-diF-Ph), CH₂-((2-CH₃)-Ph), CH₂CHOHPh, and (CH₂)₃CO-4F-Ph.

In one embodiment, the analogs have the structure of compound (28):

wherein R₁, and R₂ independently represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,heteroaryl, acyl, and heterocycle radicals. In some embodiments, R₁ andR₂ are optionally substituted. In some embodiments, some or allhydrogens in R₁ and R₂ may be substituted by deuterium. In otherembodiments, the analogs have the structure of compound (28), wherein R₁and R₂ are independently selected from the group consisting of H,C₁₋₄alkyl, C₁-4alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (28), wherein R₁and R₂ are independently selected from the group consisting of H, CH₃,CH₂Ph, CH₂-((2-Cl)-Ph), CH₂-(2-thienyl), CH₂CH₂Ph,CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-di F-Ph), CH₂-((2-CH₃)-Ph),CH₂CHOHPh, and (CH₂)₃CO-4F-Ph.

In one embodiment, the analogs have the structure of compound (29):

wherein R₁, and R₂ independently represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,heteroaryl, acyl, and heterocycle radicals. In some embodiments, R₁ andR₂ are optionally substituted. In some embodiments, some or allhydrogens in R₁ and R₂ may be substituted by deuterium. In otherembodiments, the analogs have the structure of compound (29), wherein R₁and R₂ are independently selected from the group consisting of H,C₁₋₄alkyl, C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (29), wherein R₁and R₂ are independently selected from the group consisting of H, CH₃,CH₂Ph, CH₂-((2-Cl)-Ph), CH₂-(2-thienyl), CH₂CH₂Ph,CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-di F-Ph), CH₂-((2-CH₃)-Ph),CH₂CHOHPh, and (CH₂)₃CO-4F-Ph.

In one embodiment, the analogs have the structure of compound (30):

wherein R₁, and R₂ independently represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,heteroaryl, acyl, and heterocycle radicals. In some embodiments, R₁ andR₂ are optionally substituted. In some embodiments, some or allhydrogens in R₁ and R₂ may be substituted by deuterium. In otherembodiments, the analogs have the structure of compound (30), wherein R₁and R₂ are independently selected from the group consisting of H,C₁₋₄alkyl, C₁-4alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (30), wherein R₁and R₂ are independently selected from the group consisting of H, CH₃,CH₂Ph, CH₂-((2-Cl)-Ph), CH₂-(2-thienyl), CH₂CH₂Ph,CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-di F-Ph), CH₂-((2-CH₃)-Ph),CH₂CHOHPh, and (CH₂)₃CO-4F-Ph.

In one embodiment, the analogs have the structure of compound (31):

wherein R₁, and R₂ independently represent hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, carboxyl, haloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, aralkyl, hydroxyalkyl, alkoxy, aryloxy, alkoxyalkyl,alkoxycarbonyl, aralkoxy, aralkylthio, alkanoyl, mercapto, alkylthio,arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,heteroaryl, acyl, and heterocycle radicals. In some embodiments, R₁ andR₂ are optionally substituted. In some embodiments, some or allhydrogens in R₁ and R₂ may be substituted by deuterium. In otherembodiments, the analogs have the structure of compound (31), wherein R₁and R₂ are independently selected from the group consisting of H,C₁₋₄alkyl, C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone,C₁₋₄benzyl-piperazine, and C₁₋₄alkylthienyl wherein C₁₋₄alkyl,C₁₋₄alkylphenyl, C₁₋₄alkylphenylketone, and C₁₋₄benzyl-piperazine areoptionally substituted with C₁₋₄alkyl, hydroxyl, or halo. In still otherembodiments, the analogs have the structure of compound (31), wherein R₁and R₂ are independently selected from the group consisting of H, CH₃,CH₂Ph, CH₂-((2-Cl)-Ph), CH₂-(2-thienyl), CH₂CH₂Ph,CH₂CH₂(4-N-benzyl-piperazine), CH₂-(2,4-di F-Ph), CH₂-((2-CH₃)-Ph),CH₂CHOHPh, and (CH₂)₃CO-4F-Ph.

IX. EXAMPLES

It should be understood that the description and specific examplesprovided below are intended for purposes of illustration only and arenot intended to limit the scope of the present disclosure. Examples 1 to2 illustrate synthesis of dihydrochloride salt of compound (1) startingfrom compound (1). In these examples and throughout the application thedihydrochloride salt of compound (1) is referred to as compound (2). Thefollowing examples are intended to illustrate the embodiments disclosedand are not to be construed as being limitations thereto. Additionalcompounds, other than those described below, may be prepared using thefollowing reaction schemes described above or appropriate variations ormodifications thereof.

Example 1. Synthesis of 2-Chlorobenzylamino-2-imidazoline hydriodide

To a stirred solution of 2-methylthio-2-imidazoline hydriodide (244 mg,1.00 mMol) in dry dioxane (2.0 mL) was added 2-chlorobenzylamine (141mg, 1.0 mMol). The reaction mixture was stirred for 90 min at 70 C underan atmosphere of argon. The solution was cooled to room temperature,filtered on a sintered funnel, washed with cold dioxane (2 mL) and driedunder vacuum. The white solid compound 4.HI (R₂=2-chlorobenzyl) wasobtained (242 mg, 72%) and used without further purification.

Example 2. Synthesis of 2-Chlorobenzylamino-2-imidazoline

To a stirred solution of 2-chlorobenzylamino-2-imidazoline hydriodide(242 mg, 0.72 mMol) in water (3 mL), was added 1.0 N sodium hydroxide (2mL) at 7° C. The reaction mixture was stirred for 30 min at 7° C. underargon. After that methylene chloride (5 mL) was added and the mixturestirred for another 5 min. The reaction mixture was extracted withmethylene chloride (2×2.5 mL), The organic layer was dried overanhydrous Na₂SO₄, filtered and evaporated. The resulting free base (150mg, 100%) was obtained as a viscous liquid and was used for the nextreaction without any further purification. MS(ESI) 210(M+H).

Example 3. Synthesis of Methyl-1-benzyl 4-oxo-3-piperidine carboxylate(Compound (6))

To a stirred methyl-1-benzyl 4-oxo-3-piperidine carboxylatehydrochloride (5.7 g, 20 mMol) in ethyl acetate (50 mL), was addedtriethylamine (6 mL) at 7° C. The reaction mixture was stirred for 30min at 7° C. under atmosphere of argon. The reaction mixture wasextracted with ethyl acetate (2×50 mL) washed with water (50 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and evaporated.The resulting free base residue (5, R₁=benzyl) as a viscous oil was usedin the next reaction without any further purification MS(ESI) 248(M+H)

Example 4. Synthesis of ONC902 (Compound (14))

To a solution of 2-chlorobenzylamino-2-imidazoline (150 mg, 0.72 mMol),methyl 1-benzyl 4-oxo-3-piperidine carboxylate (5, R₁=benzyl) (195 mg,0.79 mMol) in 1-butanol (2 mL) was added PPTS (10 mg) and the mixturewas stirred at room temperature for 48 h. After that the reactionmixture was refluxed at 125° C. to 130° C. for 2 h. The solvents wereremoved under vacuum, extracted with ethyl acetate (10 mL), washed withsaturated sodium bicarbonate solution (2×10 mL) and water (10 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and evaporated.The crude free base was purified by RP HPLC (10%-40% acetonitrile/water)to give ONC902 TFA salt as a white solid (228 mg, 50% yield) MS(ESI) 407(M+H).

The same process was used starting with different benzylamines toprepare various analogs, e.g., ONC903, 904, 905, and 906.

Example 5. Synthesis of ONC907 (Compound (19))

To a suspension of 60% sodium hydride (3.5 g, 88 mMol) in dry toluene(50 mL), dimethyl carbonate (4.32 g, 48.0 mMol) was added dropwise in0.5 h at room temperature under an atmosphere of nitrogen. Afteraddition of a few drops of methanol, a solution of1-tert-butoxycarbonyl-4-piperidone (4.8 g, 24 mMol) dissolved in drytoluene (20 mL) was added dropwise to the reaction mixture whilestirring at 80° C. over 1 h. The reaction mixture was stirred for 3 h atthe same temperature and then cooled to 0° C. (ice bath) and adjusted topH 6-6.5 with acetic acid. The resulting cold mixture was diluted withwater (10 mL) and adjusted to pH 8 with 5% sodium hydroxide solution.The toluene layer was separated and the aqueous layer was extracted withtoluene (20 mL). The combined organic layer was dried over anhydroussodium sulfate, and concentrated under reduced pressure The compound wasdried in vacuum to give methyl-1-tert-butoxycarbonyl-4-oxo-3-piperidinecarboxylate (5.0 g, 80%). The compound obtained was carried to nextreaction without any further purification.

2-methybenzylamino-2-imidazoline (190 mg, 1 mMol), methyl1-tert-butoxycarbonyl-4-oxo-3-piperidine carboxylate (315 mg, 1.1 mMol)in 1-butanol (2 mL) was added PPTS (10.0 mg) and the mixture was stirredat room temperature for 48 h. After that the reaction mixture wasrefluxed at 125° C. to 130° C. for 2 h. The solvents were removed undervacuum, extracted with ethyl acetate (10 mL), washed with saturatedsodium bicarbonate solution (2×10 mL) and water (10 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and evaporated. Thecrude free base was cleaved with 10% trifluoroacetic acid indichloromethane, purified by RP HPLC (10%-40% acetonitrile/water) togive ONC907 (262 mg, 50%) TFA salt as a white solid MS(ESI) 297 (M+H).

Example 6. Synthesis of ONC909 (Compound 21)

A mixture of ONC907 (100 mg, 0.2 mMol), phenylethyl bromide (55.0 mg,0.28 mMol) and potassium carbonate (150 mg, 1.0 mMol) inN,N-dimethylformamide (3 mL) was heated to 70° C. for 12 h. The solventswere removed under vacuum, extracted with ethyl acetate (10 mL), washedwith water (5 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and evaporated. The crude free base was purified by RP HPLC(10%-40% acetonitrile/water) to give ONC909 (62 mg, 50%) TFA salt as awhite solid MS(ESI) 401 (M+H).

Example 7. Synthesis of ONC908 (Compound 20)

To a solution of 2-methylbenzylamino-2-imidazoline (190.0 mg, 1.0 mmol),methyl 1-methyl 4-oxo-3-piperidine carboxylate (185.0 mg, 1.0 mMol) in1-butanol (2.0 mL) was added PPTS (10.0 mg) and the mixture was stirredat room temperature for 48 h. After that the reaction mixture wasrefluxed at 125° C. to 130° C. for 2 h. The solvents were removed undervacuum, extracted with ethyl acetate (10 mL), washed with saturatedsodium bicarbonate solution (2×10 ml) and water (10 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and evaporated. Thecrude free base was purified by HPLC 10%-40% acetonitrile and water togive ONC908 (270.0 mg., 50%) TFA salt as a white solid MS(ESI) 311(M+H).

Example 8. Synthesis of ONC201 (Compound 1)

To a stirred 800 mL saturated NaHCO₃ in a 2 L round bottom flask,compound (3) (239.7 g, 0.845 mol, 1.6 equiv) was added in portions.n-Butanol (500 mL) was added to the resulting mixture and the mixturewas stirred for 30 min and then transferred to a separating funnel. Theorganic phase, containing compound (4), was separated and transferred toa 2 L three-neck round bottom flask equipped with mechanical stirring,N₂ inlet, a thermocouple, a condenser and a Dean-Stark trap. Compound(5) (100 g, 0.528 mol, 1 equiv) and pyridinium p-toluenesulfonate (PPTS)(6.63 gm 0.026 mol, 5 mol %) were added to the contents of the flask.The resulting mixture was heated to reflux for 6 hours. Water in thereaction mixture was separated into the Dean-Stark trap as necessary.Refluxing temperature increased from 93° C. to 118° C. Reaction progresswas monitored by HPLC. When the peak area of compound (1) on HPLCremained constant with the reaction time, the reaction was stopped.

Example 9. Synthesis of Di-Salt of ONC201 (Compound (2))

Without isolation of the compound (1), the reaction mixture from EXAMPLE8 was washed with 500 mL of water and diluted with methyl tert-butylether (MTBE) (800 mL). The organic phase was washed with water (500mL×2) and transferred to a 3 L three-neck round bottom flask equippedwith mechanical stirring, N2 inlet, a thermocouple, a condenser and aDean-Stark trap. While agitating the reaction mixture, 1 N HCl indioxane-MTBE solution was added dropwise (4 N HCl in dioxane: 300 mL,1.2 mol, 2.27 equiv; MTBE: 1200 mL) until no more solid precipitated outof the reaction mixture upon addition of HCl. The reaction mixture washeated to reflux at 60-65° C. for 2 hours. Water was separated into theDean-Stark trap as necessary. Upon cooling to room temperature, thesolid precipitate was filtered through a sintered glass funnel andwashed with n-butanol-MTBE (1: 2, 600 mL) and MTBE (600 mL)respectively. The solid was dried in the vacuum oven at 65° C. overnight(16 hours) to afford 200 g yellow solid.

To a 2 L three-neck round bottom flask equipped with mechanicalstirring, N2 inlet, a thermocouple and a condenser, the above solid (200g) was added, followed by ethanol (1000 mL). The mixture was heated toreflux at 78° C. for 2 hours. Upon cooling to room temperature, thesolid was filtered through a sintered glass funnel and washed withethanol (200 mL×3). The wet solid was dried in the vacuum oven at 85° C.for 3 days until the residual solvent met specification. 120 g ofcompound (2) was obtained as a white solid in a yield of 49%, with HPLCpurity 99.7%.

It will be appreciated by those skilled in the art that changes could bemade to the exemplary embodiments shown and described above withoutdeparting from the broad inventive concept thereof. It is understood,therefore, that this invention is not limited to the exemplaryembodiments shown and described, but it is intended to covermodifications within the spirit and scope of the present invention asdefined by the claims. For example, specific features of the exemplaryembodiments may or may not be part of the claimed invention and featuresof the disclosed embodiments may be combined. Unless specifically setforth herein, the terms “a”, “an” and “the” are not limited to oneelement but instead should be read as meaning “at least one”.

It is to be understood that at least some of the figures anddescriptions of the invention have been simplified to focus on elementsthat are relevant for a clear understanding of the invention, whileeliminating, for purposes of clarity, other elements that those ofordinary skill in the art will appreciate may also comprise a portion ofthe invention. However, because such elements are well known in the art,and because they do not necessarily facilitate a better understanding ofthe invention, a description of such elements is not provided herein.

Further, to the extent that the method does not rely on the particularorder of steps set forth herein, the particular order of the stepsshould not be construed as limitation on the claims. The claims directedto the method of the present invention should not be limited to theperformance of their steps in the order written, and one skilled in theart can readily appreciate that the steps may be varied and still remainwithin the spirit and scope of the present invention.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The invention claimed is:
 1. A method of treatment comprisingadministering to a subject having ovarian cancer in need of suchtreatment a pharmaceutically acceptable amount of compound (1):

or a pharmaceutically acceptable salt thereof, wherein thepharmaceutically acceptable amount of compound (1) is administered as asalvage therapy.
 2. A method of treatment, comprising administering to asubject in need of such treatment a therapeutic agent comprisingcompound (1):

or a pharmaceutically acceptable salt thereof, wherein the treatment isfor a genitourinary cancer and wherein the genitourinary cancer isovarian cancer.